Substituted tetrahydro-2H-isoquinolin-1-one derivatives, and methods for the production and use thereof

ABSTRACT

This invention relates to compounds according to the general formula (I), where the definitions of the substituents R1, R2, Ar and X are as specified in the description, and to their physiologically tolerated salts, methods for the preparation of these compounds and their use as medicaments. 
                         
These compounds are poly(ADP-ribose) polymerase (PARP) inhibitors.

FIELD OF THE INVENTION

This application is a CON of PCT/EP05/05871 filed Jun. 1, 2005.

The invention relates to compounds according to the general formula (I),where the definitions of the substituents R1, R2, Ar and X are asspecified in the following text, and to their physiologically toleratedsalts, methods for the preparation of these compounds and their use asmedicaments.

These compounds are poly(ADP-ribose) polymerase (PARP) inhibitors.

BACKGROUND OF THE INVENTION

Inhibitory Effect on PARP

Poly(adenosine 5′-diphosphate-ribose) polymerase [poly(ADP-ribose)polymerase, PARP], which is also known as poly(ADP-ribose) synthetase(PARS), is a chromatin-bound nuclear enzyme of eukaryotic cells, ofwhich approximately 2×10⁵ molecules are present per nucleus. PARP is,according to the most recent research results, involved in thepathogenesis of various disorders, and thus inhibition of PARP enzymeactivity may have beneficial effects on the course of disorders inpreclinical animal models (Cristina Cosi, Expert Opin. Ther. Patents,2002, 12, 1047-1071 and L. Virag and C. Szabo, Pharmacol. Rev., 2002,54, 1-54). Poly(ADP-ribose) polymerase occurs in all eukaryoticorganisms with the exception of yeast, and is part of the genomesurveillance network to protect the genetic information from genotoxicinfluences. DNA damage induces the enzymatic activity ofpoly(ADP-ribose) polymerase, leading under physiological conditions torepair of the errors recognized by the enzyme in the DNA. However, inpathological situations, poly(ADP-ribose) polymerase may be stronglyactivated by free-radical oxygen species—as is the case in ischemia,hypoxia, reperfusion or in inflammatory processes—resulting inconsumption by the enzyme of large amounts of its substrate NAD. Thisdepletion of NAD is one of the reasons for the death of cells to beobserved in the affected tissue (the so-called energy crisis theory).The therapeutic use of PARP inhibitors is in the prevention or reductionof this NAD depletion in tissue. Apart from the role, described herein,in signal transmission ranging from oxidative stress in cells to NADdepletion, further cellular functions of PARP are suggested in thecurrent literature, and these might likewise play a role in themolecular mechanism of action of PARP inhibitors in pathologicalsituations (A. Chiarugi, Trends Pharmacol. Sci., 2002, 23, 122-129).Irrespective of this unresolved discussion about the molecular mechanismof action, the therapeutic efficacy of various PARP inhibitors has beenshown in several preclinical animal models: thus, for example, for acutemyocardial infarction, acute renal failure, cerebral ischemia (stroke),neurodegenerative disorders (e.g. a model of Parkinson's disease),diabetes, xenobiotic-induced hepatotoxicity, arthritis, shock lung,septic shock and as sensitizer in the chemotherapy of neoplasticdisorders (summarized in L. Virag and C. Szabo, Pharmacol. Rev., 2002,54, 1-54).

It has specifically been possible to show that PARP inhibitors bringabout morphological and functional improvements not only in acutemyocardial infarction (J. Bowes et al., Eur. J. Pharmacol., 1998, 359,143-150; L. Liaudet et al., Br. J. Pharmacol., 2001, 133, 1424-1430; N.Wayman et al., Eur. J. Pharmacol., 2001, 430, 93-100), but alsosignificantly better cardiac functions have been measured in chronicheart failure during PARP inhibitor treatment (P. Pacher, J. Am. Coll.Cardiol., 2002, 40, 1006-1016). The hypoperfusion like that which, inthe infarcted heart, brings about losses of function of the organthrough death of cells also appears in stroke at the start of the chainof events which leads to losses or complete failure of individualregions, and thus functions, of the organ. Accordingly, it has beenpossible to show the efficacy of PARP inhibitors—besides the geneticablation of the PARP-1 gene (M. J. L. Eliasson et al., Nat. Med., 1997,10, 1089-1095)—also in models of cerebral ischemia (K. Takahashi et al.,L. Cereb. Blood Flow Metab., 1997, 11, 1137-1142), of MPTP-inducedneurotoxicity (C. Cosi et al., Brain Res., 1996, 729, 264-269) and ofneuronal excitotoxicity (A. S. Mandir et al., J. Neurosci., 2000, 21,8005-8011). A further finding which is very important in connection withcardiovascular disorders is the efficacy of PARP inhibition in theischemically damaged kidney, where improvements in the filtrationfunction of the organ have likewise been found in animals treated withPARP inhibitors compared with those treated with placebo (D. R. Martinet al., Am. J. Physiol. Regulatory Integrative Comp. Physiol., 2000,279, R1834-R1840). In contrast to the acute ischemic insults of theabovementioned disorders, chronic PARP activation occurs in variouspathologies such as, for example, in diabetes. The efficacy of PARPinhibitors has been demonstrated both in preclinical models of type Idiabetes (W. L. Suarez-Pinzon et al., Diabetes, 2003, 52, 1683-1688) andin those of type II diabetes (F. G. Soriano et al., Nat. Med., 2001, 7,108-113; F. G. Soriano et al., Circulation, 2001, 89, 684-691). Thebeneficial effect of PARP inhibitors in type I diabetes is attributableto their antiinflammatory properties, which it has also been possible toshow in further preclinical models, such as of chronic colitis (H. B.Jijon et al., Am. J. Physiol. Gastrointest. Liver Physiol., 2000, 279,G641-G651), of collagen-induced arthritis (H. Kröger et al.,Inflammation, 1996, 20, 203-215) and in septic shock (B. Zingarelli etal., Shock, 1996, 5, 258-264). In addition, PARP inhibitors have asensitizing effect on tumors in chemotherapy on mice (L. Tentori et al.,Blood, 2002, 99, 2241-2244).

Background References

It has been disclosed in the literature (for example C. Cosi, ExpertOpin. Ther. patents, 2002, 12, 1047-1071; Southan et al., CurrentMedicinal Chemistry, 2003, 10, 321-340) that many different classes ofchemical compounds can be used as PARP inhibitors, such as, for example,derivatives of indoles, benzimidazoles, isoquinolinols orquinazolinones. Many of the previously disclosed PARP inhibitors arederivatives of a bi- or polycyclic basic structure.

The use of isoquinolinone derivatives as PARP inhibitors is describedfor example in WO 02/090334. The isoquinolinone derivatives describedtherein are without exception based on a basic structure in which thesecond ring of the bicycle (with carbon atoms 5, 6, 7 and 8) is inaromatic form, whereas the ring having the amide group of the bicyclemay optionally be hydrogenated in position 3 and 4. The isoquinolinonederivatives disclosed in EP-A 0 355 750, which can likewise be used asPARP inhibitors, are based on the same aromatic basic structure.

A large number of PARP inhibitors can be inferred from the generalformula (I) disclosed in WO 99/11624. Disclosed therein inter alia is atetrahydro-2H-isoquinolin-1-one derivative which has an aminoethylsubstituent in position 4. A further possibility is for the radical R⁶in formula (I) also to be aryl, although it is not mentioned that thisaryl radical optionally has further substituents. An aryl radical for R⁶is specifically described in WO 99/11624 only for examples in which thering defined by Y in the basic structure both is unsaturated and hasheteroatoms. The specific combination of a5,6,7,8-tetrahydro-2H-isoquinolin-1-one derivative which is substitutedin position 4 either directly or via a linker by an aryl or heteroarylradical is, however, neither disclosed in nor obvious from WO 99/11624.It is thus evident that the compounds of the invention are not disclosedby WO 99/11624. The present invention does not relate to compounds assuch which are explicitly disclosed in WO 99/11624.

J. Rigby et al., J. Org. Chem. 1984, 4569-4571, describe, within theframework of a general synthetic method for the cyclization of vinylisocyanates, the preparation of4-phenyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one by cyclocondensation ofan enamine and of a vinyl isocyanate. No association is made between thecompounds described in J. Rigby et al. and any use as pharmaceuticals.The present invention does not relate to the compounds explicitlydisclosed by J. Rigby et al. as such.

SUMMARY OF THE INVENTION

Since diseases, such as myocardial infarction, which can be treated byinhibition of PARP represents a serious risk for the health of humansand other mammals, there is a great need for novel pharmaceuticals whichhave an advantageous therapeutic profile for the treatment of suchdiseases. The present invention is therefore based on the object ofproviding novel compounds which have an inhibitory effect on PARP.

The object is achieved by the tetrahydro-2H-isoquinolin-1-onederivatives according to the following general formula (I).

in which the meanings are:

-   X is a single bond, O, S, NH or N(C₁-C₃-alkyl);-   R1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF₃ or    C₁-C₃-alkyl which is optionally substituted by hydroxy, chlorine,    methoxy or one, two or three fluorine atoms;-   R2 is hydrogen, fluorine, —CN, hydroxy, methoxy, —OCF₃, —NH₂,    —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂ or C₁-C₃-alkyl which is    optionally substituted by hydroxy, chlorine, methoxy or one, two or    three fluorine atoms;-   R3 is —(C₁-C₃-alkyl)-NR4R5, —SO₂NR4R5, —C(O)NR4R5, —C(H)═N—OR9,    —C(O)R6, —NHC(O)R6, —(C₁-C₃-alkyl)-NHC(O)R6, —NHSO₂R6,    —(C₁-C₃-alkyl)-NHSO₂R6 or —CH(OH)R7;-   R4 and R5 are independently of one another selected from the group    consisting of: hydrogen; unsubstituted or at least monosubstituted    C₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, heteroaryl and    heterocyclyl,    -   where the substituents are selected from the group consisting        of: aryl, heteroaryl, heterocyclyl, —O-aryl, fluorine, chlorine,        bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8, —NHC(O)(C₁-C₃-alkyl),        —NH₂, hydroxy, C₁-C₆-alkyl, C₁-C₃-alkoxy, —NH(C₁-C₃-alkyl),        —N(C₁-C₃-alkyl)₂, —NH-aryl, —NH-heteroaryl, —NH—C(O)-heteroaryl,        —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and —NH—SO₂(C₁-C₃-alkyl),    -   and the aryl, heteroaryl and heterocyclyl fragments of these        substituents may in turn be at least monosubstituted by        fluorine, chlorine, bromine, oxo, —CF₃, —OCF₃, —NO₂, —CN, aryl,        heteroaryl, —NHC(O)(C₁-C₃-alkyl), —COOH, hydroxy, C₁-C₃-alkyl,        C₁-C₃-alkoxy, —SO₂NH₂, —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂,        —C(O)NH₂, —C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂,        —SO₂(C₁-C₃-alkyl), —NH₂, —NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂;        or    -   R4 and R5 form together with the nitrogen atom to which they are        bonded unsubstituted or at least monosubstituted heterocyclyl,    -   where the substituents are selected from the group consisting        of: aryl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine,        bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8, —NHC(O)(C₁-C₃-alkyl),        —NH₂, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —NH(C₁-C₃-alkyl),        —N(C₁-C₃-alkyl)₂, —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and        —NH—SO₂(C₁-C₃-alkyl),    -   and, of these substituents, aryl, heterocyclyl and heteroaryl in        turn may be at least monosubstituted by fluorine, chlorine,        bromine, hydroxy, C₁-C₃-alkyl or C₁-C₃-alkoxy;-   R6 is unsubstituted or at least monosubstituted C₁-C₆-alkyl, phenyl,    heteroaryl or heterocyclyl,    -   where the substituents are selected from the group consisting        of:

fluorine, chlorine, bromine, aryl, heterocyclyl, heteroaryl, —CF₃,—OCF₃, —NO₂, —CN, —C(O)R8, —NHC(O)(C₁-C₃-alkyl), —NH₂, hydroxy,C₁-C₃-alkyl, C₁-C₃-alkoxy, —O-heteroaryl, —O-aryl, —NH(C₁-C₃-alkyl),—N(C₁-C₃-alkyl)₂, —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and —NH—SO₂(C₁-C₃-alkyl),

-   -   and the aryl, heterocyclyl and heteroaryl fragments of these        substituents may in turn be at least monosubstituted by        fluorine, chlorine, bromine, hydroxy, C₁-C₃-alkyl or        C₁-C₃-alkoxy;

-   R7 is selected from the group consisting of:    -   hydrogen; unsubstituted or at least monosubstituted C₁-C₆-alkyl,        phenyl and heteroaryl,    -   where the substituents are selected from the group consisting        of:    -   fluorine, chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8,        —NHC(O)(C₁-C₃-alkyl), —NH₂, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,        —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂NH₂, —SO₂(C₁-C₃-alkyl)        and —NH—SO₂(C₁-C₃-alkyl);

-   R8 is C₁-C₃-alkoxy, —O-phenyl, C₁-C₃-alkyl, —NH₂, —NH(C₁-C₃-alkyl),    —N(C₁-C₃-alkyl)₂ or phenyl,    -   and the above phenyl fragments may in turn be at least        monosubstituted by fluorine, chlorine, bromine, oxo, —CF₃,        —OCF₃, —NO₂, —CN, aryl, heteroaryl, —NHC(O)(C₁-C₃-alkyl), —COOH,        hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂,        —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂,        —C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl),        —NH₂, —NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂;

-   R9 is selected from the group consisting of:    -   hydrogen; unsubstituted or at least monosubstituted C₁-C₆-alkyl        and phenyl,    -   where the substituents are selected from the group consisting        of:    -   fluorine, chlorine, bromine, aryl, heterocyclyl, heteroaryl,        —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8, —NHC(O)(C₁-C₃-alkyl),        C₁-C₃-alkyl, C₁-C₃-alkoxy, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂,        —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and —NH—SO₂(C₁-C₃-alkyl),    -   and, of these substituents, aryl, heterocyclyl and heteroaryl        may in turn be at least monosubstituted by fluorine, chlorine,        bromine, C₁-C₃-alkyl or C₁-C₃-alkoxy;

-   Ar is unsubstituted or at least monosubstituted aryl or heteroaryl,    where the substituents are selected from the group consisting of:    fluorine, chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8, —NH₂,    —NHC(O)(C₁-C₆-alkyl), hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy,    —CH₂—CH₂—CH₂—, —CH₂—O—C(O)—, —CH₂—C(O)—O—, —CH₂—NH—C(O)—,    —CH₂—N(CH₃)—C(O)—, —CH₂—C(O)—NH—, —NH(C₁-C₆-alkyl),    —N(C₁-C₆-alkyl)₂, —SO₂(C₁-C₆-alkyl), heterocyclyl, heteroaryl, aryl    and R3,    -   and, of these substituents, heterocyclyl, aryl and heteroaryl        may in turn be at least monosubstituted by C₁-C₆-alkyl,        C₁-C₆-alkoxy, fluorine, chlorine, bromine, trifluoromethyl,        trifluoromethoxy or OH;

-   heteroaryl is a 5 to 10-membered, aromatic, mono- or bicyclic    heterocycle which comprises one or more heteroatoms selected from N,    O and S;

-   aryl is a 5 to 10-membered, aromatic, mono- or bicycle;

-   heterocyclyl is a 5 to 10-membered, non-aromatic, mono- or bicyclic    heterocycle which comprises one or more heteroatoms selected from N,    O and S;

-   or a physiologically tolerated salt thereof;    provided that Ar is not unsubstituted phenyl when X is a single    bond.

The above meanings of the substituents R¹ to R⁸, X, Ar, heteroaryl,heterocyclyl and aryl are the basic meanings (definitions) of therespective substituents.

DETAILED DESCRIPTION

The tetrahydro-2H-isoquinolin-1-one derivatives of the inventionaccording to formula (I) differ in an advantageous manner frompreviously disclosed isoquinolin-1-one-based PARP inhibitors because,firstly, the second ring of the isoquinolinone basic structure is inhydrogenated form and, secondly, an aryl or heteroaryl substituent ispresent in position 4 on the isoquinolinone basic structure eitherdirectly or via the linker X. The majority of previously disclosedisoquinolin-1-one-based PARP inhibitors have (virtually) planar aromaticbasic structures. Many of these planar PARP inhibitors may haveDNA-binding or DNA-intercalating properties which are responsible forthe suboptimal safety profile (cf. Southan et al., Current MedicinalChemistry 2003, 10, 321-340). Since the isoquinolinone basic structurein the compounds of the invention is no longer planar in position 5, 6,7 and 8 owing to its saturation, these molecules display an advantageoussafety profile compared with the planar aromatic basic structures. Thepresence of an aryl or heteroaryl substituent in position 4 of the basicstructure has an additional beneficial effect on the PARP-inhibitoryeffect of the compounds of the invention.

Where groups, fragments, radicals or substituents such as, for example,aryl, heteroaryl, alkyl, alkoxy etc. are present more than once in thecompounds according to formula (I), they all have independently of oneanother the abovementioned meanings and may thus in each (individual)case have either an identical or a mutually independent meaning. Thefollowing statements apply to (for example) aryl and any other radicalirrespective of its designation as aryl group, substituent, fragment orradical. A further example is the —N(C₁-C₃-alkyl)₂ group in which thetwo alkyl substituents may be either identical or different (for exampletwice ethyl or once propyl and once methyl).

Where a substituent, for example aryl, in the above definitions ofcompounds according to formula (I) may be unsubstituted or at leastmonosubstituted by a group of further substituents, for exampleC₁-C₆-alkyl, C₁-C₆-alkoxy, halogen etc., then the selection in thosecases where aryl is polysubstituted takes place from the series offurther substituents independently of one another. Thus, for example,when aryl is disubstituted, all combinations of the further substituentsare included. Aryl may thus be for example disubstituted with ethyl,aryl may in each case be monosubstituted with methyl and ethoxy, arylmay in each case be monosubstituted with ethyl and fluorine, aryl may bedisubstituted with methoxy, etc.

Alkyl radicals may be either linear or branched, acyclic or cyclic. Thisalso applies when they are a part of another group such as, for example,alkoxy groups (C₁-C₁₀-alkyl-O—), alkoxycarbonyl groups or amino groups,or if they are substituted.

Examples of alkyl groups are: methyl, ethyl, propyl, butyl, pentyl,hexyl, heptyl, octyl, nonyl or decyl. Included therein are both the nisomers of these radicals and isopropyl, isobutyl, isopentyl, sec-butyl,tert-butyl, neopentyl, 3,3-dimethylbutyl etc. Unless describedotherwise, the term alkyl additionally includes alkyl radicals which areunsubstituted or optionally substituted by one or more further radicals,for example 1, 2, 3 or 4 identical or different radicals, such as, forexample, aryl, heteroaryl, alkoxy or halogen. It is moreover possiblefor the additional substituents to occur in any desired position of thealkyl radical. The term alkyl also includes cycloalkyl andcycloalkylalkyl (alkyl which is in turn substituted by cycloalkyl),where cycloalkyl has at least 3 carbon atoms. Examples of cycloalkylradicals are: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl, cyclooctyl, cyclononyl and cyclodecyl. The ring systems mayalso, where appropriate, be polycyclic, such as decalinyl, norbornanyl,bornanyl or adamantanyl. The cycloalkyl radicals may be unsubstituted oroptionally substituted by one or more further radicals as mentionedabove by way of example for the alkyl radicals.

Examples of alkenyl and alkynyl groups are: vinyl, 1-propenyl,2-propenyl (allyl), 2-butenyl, 2-methyl-2-propenyl, 3-methyl-2-butenyl,ethynyl, 2-propynyl (propargyl), 2-butynyl or 3-butynyl. The termalkenyl here expressly also includes cycloalkenyl radicals andcycloalkenylalkyl radicals (alkyl which is substituted by cycloalkenyl)which comprise at least three carbon atoms. Examples of cycloalkenylare: cyclopentenyl, cyclohexenyl, cycloheptenyl and cyclooctenyl.

The alkenyl radicals may have one to three conjugated or non-conjugateddouble bonds (that is to say also alk-dienyl and alk-trienyl radicals),preferably one double bond in a linear or branched chain, and the sameapplies to the triple bonds for alkynyl radicals. The alkenyl andalkynyl radicals may be unsubstituted or optionally substituted by oneor more further radicals as mentioned above by way of example for thealkyl radicals.

Unless stated otherwise, the aforementioned aryl, heteroaryl andheterocyclyl radicals may either unsubstituted or have one or more, forexample 1, 2, 3 or 4 further, of the aforementioned substituents in anydesired position. For example, the substituent in monosubstituted phenylradicals may be in position 2, 3 or 4, the substituents in disubstitutedphenyl radicals may be in the 2,3 position, 2,4 position, 2,5 position,2,6 position, 3,4 position or 3,5 position. The substituents intrisubstituted phenyl radicals may be in the 2,3,4 position, 2,3,5position, 2,3,6 position, 2,4,5 position, 2,4,6 position or the 3,4,5position. The substituents in tetrasubstituted phenyl radicals may be inthe 2,3,4,5 position, the 2,3,4,6 position or in the 2,3,5,6 position.

The aforementioned and the following definitions relating to monovalentradicals apply in exactly the same way to divalent radicals such asphenylene, naphthylene or heteroarylene. These divalent radicals(fragments) may be linked to the adjacent groups for any desired ringcarbon atom. In the case of phenylene radicals, this may be in the 1,2position (ortho-phenylene), 1,3 position (meta-phenylene) or 1,4position (para-phenylene). In the case of a 5-membered aromatic systemcomprising a heteroatom, such as, for example, thiophene or furan, thetwo free bonds may be in the 2,3 position, 2,4 position, 2,5 position or3,4 position. A divalent radical derived from a 6-membered aromaticsystem having a heteroatom, such as, for example, pyridine, may be a2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-pyridinediyl radical. In the case ofnonsymmetrical divalent radicals, the present invention also includesall positional isomers, i.e. in the case of, for example, a2,3-pyridinediyl radical the compound in which one adjacent group islocated in position 2 and the other adjacent group is located inposition 3 is included just as much as the compound in which oneadjacent group is located in position 3 and the other adjacent group islocated in position 2.

Unless stated otherwise, heteroaryl radicals heteroarylene radicals,heterocyclyl radicals and heterocyclylene radicals, and rings which areformed by two groups bonded to nitrogen, are preferably derived fromcompletely saturated, partly or wholly unsaturated heterocycles (i.e.heterocycloalkanes, heterocycloalkenes, heteroaromatics) which comprise1, 2, 3 or 4 heteroatoms which may be either different or identical.They are preferably derived from heterocycles which comprise 1, 2 or 3,particularly preferably 1 or 2, heteroatoms which may be identical ordifferent. Unless stated otherwise, the heterocycles are mono- orpolycyclic, for example monocyclic, bicyclic or tricyclic. They arepreferably monocyclic or bicyclic. 5-Membered, 6-membered or 7-memberedrings are preferred, and 5-membered or 6-membered rings are particularlypreferred. In the case of polycyclic heterocycles having 2 and moreheteroatoms, these may occur all in the same ring or be distributed overa plurality of rings.

Radicals referred to as heteroaryl in the present invention are derivedfrom monocyclic or bicyclic aromatic heterocycles. Examples ofheteroaryl are: pyrrolyl, furanyl (═furyl), thiophenyl (═thienyl),imidazolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,3-oxazolyl(═Oxazolyl), 1,2-oxazolyl (═isoxazolyl), oxadiazolyl, 1,3-thiazolyl(═thiazolyl), 1,2-thiazolyl (═isothiazolyl), tetrazolyl, pyridinyl(═pyridyl), pyridazinyl, pyrimidinyl, pyrazinyl, 1,2,3-triazinyl,1,2,4-triazinyl, 1,3,5-triazinyl, 1,2,4,5-tetrazinyl, indazolyl,indolyl, benzothiophenyl, benzofuranyl, benzothiazolyl, benzimidazolyl,quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, phthalazinyl,thienothiophenyl, 1,8-naphthyridinyl, other naphthyridinyls, pteridinylor thiazolo[3,2-b][1,2,4]-triazolyl. Where the systems arenon-monocyclic, also included for the second ring for each of theabovementioned heteroaryls is the saturated form (perhydro form) or thepartly unsaturated form (for example the dihydro form or tetrahydroform) or the maximally unsaturated (nonaromatic) form, as long as therespective forms are known and stable. The term heteroaryl thus includesin the present invention for example also bicyclic radicals in whicheither both rings are aromatic or bicyclic radicals in which only onering is aromatic. Such examples of heteroaryl are: 3H-indolinyl,2(1H)-quinolinonyl, 4-oxo-1,4-dihydroquinolinyl, 2H-1-oxoisoquinolyl,1,2-dihydroquinolinyl, 3,4-dihydroquinolinyl, 1,2-dihydroisoquinolinyl,3,4-dihydroisoquinolinyl, chromonyl, chromanyl, 1,3-benzodioxolyl,oxindolyl, 1,2,3,4-tetrahydroisoquinolinyl, 5,6-dihydroquinolinyl,5,6-dihydroisoquinolyl, 5,6,7,8-tetrahydroquinolinyl or5,6,7,8-tetrahydroisoquinolyl.

Radicals referred to as heterocyclyl in the present invention arederived from monocyclic or bicyclic nonaromatic heterocycles.Nonaromatic heterocycles mean hereinafter in particularheterocycloalkanes (completely saturated heterocycles) andheterocycloalkenes (partly unsaturated heterocycles). In the case of theheterocycloalkenes, also included are compounds having two or moredouble bonds, which may optionally also be conjugated together. Examplesof heterocyclyl are: pyrrolidinyl, piperidinyl, piperazinyl,imidazolidinyl, pyrazolidinyl, isothiazolidinyl, thiazolidinyl,isoxazolidinyl, oxazolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl,1,3-dioxolanyl, 1,4-dioxinyl, pyranyl, thiopyranyl,tetrahydro-1,2-oxazinyl, tetrahydro-1,3-oxazinyl, morpholinyl,thiomorpholinyl, 1,2-thiazinyl, 1,3-thiazinyl, 1,4-thiazinyl, azepinyl,1,2-diazepinyl, 1,3-diazepinyl, 1,4-diazepinyl, 1,3-oxazepinyl,1,3-thiazepinyl, azepanyl, 2-oxoazepanyl, 1,2,3,4-tetrahydropyridinyl,1,2-dihydropyridinyl, 1,4-dihydropyridinyl, 1,2,3,6-tetrahydropyridinyl,4(3H)-pyrimidonyl, 1,4,5,6-tetrahydropyrimidinyl, 2-pyrrolinyl,3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, 3,4-dihydro-2H-pyranyl,dihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl anddihydrothiopyranyl. The degree of saturation of heterocyclic groups isindicated in the respective definition.

Substituents derived from these heterocycles may be linked via anysuitable carbon atom, and be provided with further substituents.Radicals derived from nitrogen-containing heterocycles may have ahydrogen atom or another substituent on the corresponding nitrogen atom.Examples include pyrrole, imidazole, pyrrolidine, morpholine, piperazineradicals etc. These nitrogen-containing heterocyclic radicals may alsobe linked via the ring nitrogen atom, especially if the correspondingheterocyclic radical is linked to a carbon atom. For example, a thienylradical may be in the form of 2-thienyl or 3-thienyl, a piperidinylradical in the form of 1-piperidinyl (piperidino), 2-piperidinyl,3-piperidinyl or 4-piperidinyl. Suitable nitrogen-containingheterocycles may also be in the form of N-oxides or of quaternary saltswhich have a counter ion which is derived from a physiologicallyacceptable acid. For example, pyridinyl radicals may be in the form ofpyridine N-oxides. Suitable sulfur-containing heterocycles may also bein the form of S-oxide or S—S-dioxide.

Radicals referred to as aryl in the present invention are derived frommonocyclic or bicyclic aromatic systems which comprise no ringheteroatoms. Where the systems are non-monocyclic, also for the secondring in the term aryl is the saturated form (perhydro form) or thepartly unsaturated form (for example the dihydro form or tetrahydroform), as long as the respective forms are known and stable. The termaryl also includes in the present invention for example bicyclicradicals in which either both rings are aromatic or bicyclic radicals inwhich only one ring is aromatic. Examples of aryl are: phenyl, naphthyl,indanyl, 1,2-dihydronaphthenyl, 1,4-dihydronaphthenyl, indenyl or1,2,3,4-tetrahydronaphthyl.

Arylalkyl (such as aryl-(C₁-C₆-alkyl)-) means that an alkyl radical(such as C₁-C₆-alkyl) is in turn substituted by an aryl radical.Heteroarylalkyl (such as heteroaryl-(C₁-C₆-alkyl)-) means that an alkylradical (such as C₁-C₆-alkyl) is in turn substituted by a heteroarylradical. Heterocyclylalkyl (such as heterocyclyl-(C₁-C₆-alkyl)-) meansthat an alkyl radical (such as C₁-C₆-alkyl) is in turn substituted by aheterocyclyl radical. Reference is made to the foregoing definitions forthe definitions and possible substitutions of alkyl, heteroaryl,heterocyclyl and aryl.

Where bivalent substituents in which the two free valences are notlocated on the (carbon) atom are defined in the present invention, suchas, for example, —CH₂—CH₂—CH₂— (propylene) or —CH₂—O—C(O)— in the caseof Ar, this means that this bivalent substituent is linked with bothfree valences to the same radical (for example Ar) and thus brings aboutthe formation of a (further) ring. The bivalent substituent is usuallylinked to different atoms of the corresponding radical, but may whereappropriate—if this is possible—also be linked by the two free valencesto the same atom of the radical.

Halogen is fluorine, chlorine, bromine or iodine, is preferablyfluorine, chlorine or bromine, and is particularly preferably fluorineor chlorine.

The present invention includes all stereoisomeric forms of compoundsaccording to formula (I). Asymmetric carbon atoms in compounds accordingto formula (I) may have independently of one another S configurations orR configurations. The invention includes all possible enantiomers anddiastereomers and mixtures of two or more stereoisomers, for examplemixtures of enantiomers and/or diastereomers, in all amounts and ratios.It is thus possible for compounds of the present invention which existas enantiomers to be in enantiopure form, both as dextrorotatory andlevorotatory antipodes, in the form of racemates and in the form ofmixtures of the two enantiomers in all ratios. In the case of cis/transisomers, the invention includes both the cis form and the trans form,and mixtures of these forms in all ratios. The present invention relatesto all these forms. Preparation of the individual stereoisomers ispossible if desired by separating a mixture by conventional methods, forexample by chromatography or crystallization, through the use ofstereochemically pure starting materials for the synthesis or bystereoselective synthesis. It is also possible alternatively to carryout a derivatization before separating the stereoisomers. Separation ofa mixture of stereoisomers can be carried out with the compounds of theformula (I) or with the appropriate intermediates during the synthesis.The present invention further includes also all tautomeric forms ofcompounds according to formula (I), in particular keto/enol tautomerism,i.e. the corresponding compounds may be either in their keto form or intheir enol form or in mixtures thereof in all the ratios.

Where the compounds according to formula (I) comprise one or more acidicor basic groups, the present invention also includes the correspondinglyphysiologically or toxicologically acceptable salts.

Physiologically acceptable salts are, because their solubility in wateris greater than that of the starting or basic compounds, particularlysuitable for medical applications. These salts must have aphysiologically acceptable anion or cation. Suitable physiologicallyacceptable acid addition salts of the compounds of the invention aresalts of inorganic acids such as hydrochloric acid, hydrobromic,phosphoric, metaphosphoric, nitric, sulfonic and sulfuric acids, andorganic acids such as, for example, acetic acid, theophyllineaceticacid, methylenebis-b-oxynaphthonic, benzenesulfonic, benzoic, citric,ethanesulfonic, salicylic, fumaric, gluconic, glycolic, isethionic,lactic, lactobionic, maleic, malic, methanesulfonic, succinic,p-toluenesulfonic, tartaric and trifluoroacetic acids. Suitablepharmaceutically acceptable basic salts are ammonium salts, alkali metalsalts (such as sodium and potassium salts) and alkaline earth metalsalts (such as magnesium and calcium salts).

Salts with a pharmaceutically unacceptable anion likewise belong withinthe framework of the invention as useful intermediates for preparing orpurifying pharmaceutically acceptable salts and/or for use innon-therapeutic, for example in vitro, applications.

Where compounds of the formula (I) comprise both acidic and basic groupsin the same molecule, the present invention includes—in addition to thesalt forms detailed previously—also inner salts or betaines(zwitterions).

The corresponding salts of the compounds according to formula (I) can beobtained by conventional methods which are known to the skilled worker,for example by reacting with an organic or inorganic acid or base in asolvent or dispersant, or by anion or cation exchange with other salts.

The present invention additionally includes all solvates of compoundsaccording to formula (I), for example hydrates or adducts with alcohol,active metabolites of compounds according to formula (I), andderivatives which comprise a physiologically acceptable group which canbe eliminated, for example esters or amides.

The term “physiologically functional derivative” used herein refers toany physiologically acceptable derivative of a compound of the inventionof the formula I, e.g. an ester which, on administration to a mammalsuch as, for example, a human, is able (directly or indirectly) to forma compound of the formula I or an active metabolite thereof.

Physiologically functional derivatives also include prodrugs of thecompounds of the invention. Such prodrugs may be metabolized in vivo toa compound of the invention. These prodrugs may themselves be active ornot and the present invention likewise relates to them.

The compounds of the invention may also exist in various polymorphousforms, e.g. as amorphous and crystalline polymorphous forms. Allpolymorphous forms of the compounds of the invention belong within theframework of the invention and are a further aspect of the invention.

Preferred compounds of the general formula (I) are those compounds inwhich one, more than one or all of the aforementioned substituents R¹ toR⁸, X, Ar, heteroaryl, heterocyclyl and aryl have independently of oneanother the meanings (definitions) detailed below, and the presentinvention relates to all possible combinations of preferred, morepreferred, much more preferred, even much more preferred andparticularly preferred meanings (definitions), likewise in combinationwith the substituents in their basic meaning.

-   X is preferably a single bond, NH or N(C₁-C₃-alkyl);-   X is particularly preferably a single bond or NH;-   R1 is preferably hydrogen or C₁-C₃-alkyl which is optionally    substituted by hydroxy, chlorine, methoxy or one, two or three    fluorine atoms;-   R1 is particularly preferably hydrogen or C₁-C₃-alkyl;-   R2 is preferably hydrogen, fluorine, —OCF₃, hydroxy, methoxy, —NH₂    or C₁-C₃-alkyl;-   R2 is particularly preferably hydrogen;-   Ar is preferably unsubstituted or at least monosubstituted phenyl or    heteroaryl,    -   where the substituents are selected from the group consisting        of: fluorine, chlorine, —CF₃, —OCF₃, C(O)(C₁-C₃-alkyl), —NH₂,        —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,        —CH₂—CH₂—CH₂—, —CH₂—O—C(O)—, —CH₂—C(O)—O—, —CH₂—NH—C(O)—,        —CH₂—N(CH₃)—C(O)—, —CH₂—C(O)—NH—, —NH(C₁-C₃-alkyl),        —N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), heterocyclyl, heteroaryl,        aryl and R3,    -   and, of these substituents, heterocyclyl and heteroaryl in turn        may be at least monosubstituted by C₁-C₃-alkyl, C₁-C₃-alkoxy,        fluorine, chlorine, bromine, trifluoromethyl, trifluoromethoxy        or OH;-   Ar is more preferably unsubstituted or at least monosubstituted    phenyl, thienyl, furanyl or pyridinyl,    -   where the substituents are selected from the group consisting        of:

fluorine, chlorine, —CF₃, —OCF₃, C(O)(C₁-C₃-alkyl), —NH₂,—NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —CH₂—CH₂—CH₂—,—CH₂—O—C(O)—, —CH₂—C(O)—O—, —CH₂—NH—C(O)—, —CH₂—N(CH₃)—C(O)—,—CH₂—C(O)—NH—, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl) andR3;

-   Ar is much more preferably monosubstituted phenyl, thienyl, furanyl    or pyridinyl,    -   where the substituent is selected from the group consisting of:    -   fluorine, chlorine, —CF₃, —OCF₃, C(O)(C₁-C₃-alkyl), —NH₂,        —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,        —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl) and R3;    -   and the substituent and X are in the meta position relative to        one another; this is to be understood to mean that the fragment        Ar of the compound according to formula (I)—with the above        definitions of Ar—is substituted by one substituent, and Ar is        in turn substituted by X in the position meta to this        substituent. The meta substitution does not depend on the        position of the heteroatom of Ar.-   Ar is even much more preferably monosubstituted phenyl, thienyl,    furanyl or pyridinyl,    -   where the substituent is selected from the group consisting of:    -   fluorine, chlorine, —OCF₃, —C(O)CH₃, —NHC(O)CH₃, hydroxy,        —N(CH₃)₂, ethoxy, —SO₂CH₃ and R3;    -   and the substituent and X are in the meta position relative to        one another;-   Ar is particularly preferably furanyl monosubstituted by R3, and R3    and X are in the meta position relative to one another.-   R3 is preferably —CH₂—NR4R5, —SO₂NR4R5, —C(O)NR4R5, —CH₂NHC(O)R6,    —CH₂—NHSO₂R6 or —CH(OH)R7;-   R3 is more preferably —CH₂—NR4R5, —C(O)NR4R5, —CH₂—NHC(O)R6,    CH₂—NHSO₂R6 or —CH(OH)R7;-   R3 is much more preferably —CH₂—NR4R5, —C(O)NR4R5 or —CH(OH)R7;-   R3 is particularly preferably —CH₂—NR4R5;-   R4 and R5 are independently of one another preferably selected from    the group consisting of: hydrogen; unsubstituted or at least    monosubstituted C₁-C₁₀-alkyl, C₂-C₆-alkenyl, phenyl, indanyl,    heterocyclyl and heteroaryl, where the substituents are selected    from the group consisting of: phenyl, heteroaryl, heterocyclyl,    —O-phenyl, fluorine, —CN, —C(O)NH₂, —C(O)(C₁-C₃-alkyl),    —C(O)-phenyl, —N(C₁-C₃-alkyl), —C(O)-phenyl, —N(C₁-C₃-alkyl)₂,    —NH(C₁-C₃-alkyl), —NH₂, —NH-heteroaryl, —NH—C(O)-heteroaryl,    C₁-C₆-alkyl, C₁-C₃-alkoxy and hydroxy,    -   and the phenyl, heterocyclyl and heteroaryl fragments of these        substituents may in turn be at least monosubstituted by        fluorine, chlorine, bromine, oxo, —CF₃, —OCF₃, —NO₂, —CN,        phenyl, pyridinyl, —NHC(O)(C₁-C₃-alkyl), —COOH, hydroxy,        C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂, —SO₂NH(C₁-C₃-alkyl),        —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂, —C(O)NH(C₁-C₃-alkyl),        —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), —NH₂, —NH(C₁-C₃-alkyl)        or N(C₁-C₃-alkyl)₂; or    -   R4 and R5 form together with the nitrogen atom to which they are        bonded unsubstituted or at least monosubstituted heterocyclyl,    -   where the substituents are selected from the group consisting        of: phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine,        —C(O)(C₁-C₃-alkyl), —C(O)-phenyl and hydroxy,    -   and the phenyl, heterocyclyl and heteroaryl fragments of these        substituents may in turn be at least monosubstituted by fluorine        or C₁-C₃-alkyl;-   R4 is more preferably selected from the group consisting of:    hydrogen, unsubstituted or at least monosubstituted C₁-C₁₀-alkyl,    C₂-C₆-alkenyl, phenyl, indanyl, heterocyclyl and heteroaryl,    -   where the substituents are selected form the group consisting        of: phenyl, heteroaryl, heterocyclyl, —O-phenyl, fluorine, —CN,        —C(O)NH₂, —C(O)(C₁-C₃-alkyl), —C(O)-phenyl, —N(C₁-C₃-alkyl)₂,        —NH(C₁-C₃-alkyl), —NH₂, —NH-heteroaryl, —NH—C(O)-heteroaryl,        C₁-C₆-alkyl, C₁-C₃-alkoxy and hydroxy,    -   and the phenyl, heterocyclyl and heteroaryl fragments of these        substituents may in turn by fluorine, chlorine, bromine, oxo,        —CF₃, —OCF₃, —NO₂, —CN, phenyl, pyridinyl, —NHC(O)(C₁-C₃-alkyl),        —COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂,        —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂,        —C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl),        —NH₂, —NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂; and R5 is hydrogen;        or    -   R4 and R5 form together with the nitrogen atom to which they are        bonded unsubstituted or at least monosubstituted heterocyclyl,    -   where the substituents are selected from the group consisting        of: phenyl, heteroaryl, heterocyclyl, oxo, fluorine, chlorine,        —C(O)(C₁-C₃-alkyl), —C(O)-phenyl and hydroxy,    -   and the phenyl, heterocyclyl and heteroaryl fragments of these        substituents may in turn be at least monosubstituted by fluorine        or C₁-C₃-alkyl;-   R4 is much more preferably selected from the group consisting of;    hydrogen; unsubstituted or at least monosubstituted C₁-C₁₀-alkyl,    cyclohexenyl, indanyl, phenyl, pyrrolidinyl, pyrrolyl, pyrazolyl,    furanyl and piperidinyl,    -   where the substituents are selected from the group consisting        of: fluorine, —CN, —C(O)NH₂, —O-phenyl, —C(O)-phenyl, —N(CH₃)₂,        C₁-C₃-alkyl, C₁-C₃-alkoxy, hydroxy, unsubstituted or at least        monosubstituted phenyl, pyridinyl, thienyl, pyrimidinyl,        imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl,        morpholinyl, pyrrolidinyl, 1,3-benzodioxolyl, piperidinyl,        tetrahydropyranyl, triazolyl, thiazolyl, thiazolidinyl,        isoxazolyl and dihydroisoxazolyl, of which the substituents are        in turn selected from the group consisting of: fluorine,        chlorine, oxo, CF₃, —OCF₃, —NO₂, phenyl, pyridinyl, —NHC(O)CH₃,        —COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂, —C(O)NH₂ and        —NH(CH₃)₂; and R5 is hydrogen; or    -   R4 and R5 form together with the nitrogen atom to which they are        bonded a radical selected from the group consisting of:        unsubstituted or at least monosubstituted piperidinyl,        pyrrolidinyl, morpholinyl and piperazinyl,    -   where the substituents are selected from the group consisting        of: fluorine, —C(O)(C₁-C₃-alkyl), oxo, C₁-C₃-alkyl, hydroxy,        unsubstituted or at least monosubstituted phenyl, imidazolyl,        pyridinyl, pyrimidinyl, piperidinyl and pyrrolidinyl, the        substituents of which are in turn fluorine or C₁-C₃-alkyl;-   R4 is particularly preferably unsubstituted or at least    monosubstituted C₁-C₆-alkyl,    -   where the substituents are selected from the group consisting        of: —N(CH₃)₂, hydroxy, unsubstituted or at least monosubstituted        phenyl, pyridinyl, imidazolyl, indolyl, benzimidazolyl,        pyrazolyl and pyrrolidinyl, the substituents of which are in        turn selected from the group consisting of: —NHC(O)CH₃,        C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂ and —C(O)NH₂; and R5 is        hydrogen; or    -   R4 and R5 form together with the nitrogen atom to which they are        bonded a radical selected from the group consisting of:        unsubstituted or at least monosubstituted pyrrolidinyl,        piperidinyl and piperazinyl, where the substituents are selected        from the group consisting of: C₁-C₃-alkyl, hydroxy and        pyrrolidinyl;-   R6 is preferably unsubstituted or at least monosubstituted    C₁-C₆-alkyl, phenyl or heteroaryl,    -   where the substituents are selected from the group consisting        of: fluorine, chlorine, bromine, —CF₃, —OCF₃,        —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,        —O-heteroaryl, phenyl, —NH₂, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂        and heterocyclyl,    -   and the phenyl, heteroaryl and heterocyclyl fragments of these        substituents may in turn be at least monosubstituted by        fluorine, chlorine, bromine, hydroxy, C₁-C₃-alkyl or        C₁-C₃-alkoxy;-   R6 is more preferably —CF₃ or unsubstituted or at least    monosubstituted C₁-C₆-alkyl, pyridinyl, furanyl or phenyl,    -   where the substituents are selected from the group consisting        of: fluorine, —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl,        C₁-C₃-alkoxy and —O-pyridinyl;-   R6 is particularly preferably C₁-C₆-alkyl, pyridinyl, —CF₃, furanyl    or phenyl, and phenyl may optionally be substituted by —NH(O)CH₃,    —O-pyridinyl or methoxy;-   R7 is preferably selected from the group consisting of:    -   hydrogen; unsubstituted or at least monosubstituted C₁-C₆-alkyl,        phenyl and pyridinyl,    -   where the substituents are selected from the group consisting        of: fluorine, chlorine, bromine, hydroxy, C₁-C₃-alkyl and        C₁-C₃-alkoxy;-   R7 is particularly preferably hydrogen;-   R9 is preferably hydrogen or pyrrolidinylethyl;-   aryl is preferably phenyl, indanyl or naphthyl;-   aryl is more preferably phenyl or indanyl;-   aryl is particularly preferably phenyl;-   heteroaryl is preferably pyridinyl, thienyl, pyrimidinyl,    imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl,    1,3-benzodioxolyl, triazolyl, thiazolyl, isoxazolyl, pyrrolyl,    pyrazinyl, oxazolyl, pyridazinyl, quinolinyl, isoquinolyl,    benzofuranyl, 3-oxo-1,3-dihydroisobenzofuranyl or    4,5,6,7-tetrahydrobenzothiazolyl;-   heteroaryl is more preferably pyridinyl, thienyl, pyrimidinyl,    imidazolyl, furanyl, benzimidazolyl, pyrazolyl, thiazolyl,    isoxazolyl, pyrrolyl, pyrazinyl, 3-oxo-1,3-dihydroisobenzofuranyl or    4,5,6,7-tetrahydrobenzothiazolyl-   heteroaryl is particularly preferably pyridinyl, thienyl, pyrazolyl,    furanyl or benzimidazolyl;-   heterocyclyl is preferably morpholinyl, pyrrolidinyl, piperidinyl,    tetrahydropyranyl, thiazolidinyl, dihydroisoxazolyl, piperazinyl or    tetrahydrofuranyl;-   heterocyclyl is particularly preferably morpholinyl, pyrrolidinyl,    piperidinyl or piperazinyl;    examples of embodiments with preferred compounds of the general    formula (I) with reference to the meanings (definitions) described    above are:-   i) R1 to R7, X, Ar, heteroaryl and heterocyclyl each have their    preferred meaning; or-   ii) R1 has its preferred meaning and all other substituents have    their basic meaning; or-   iii) R2 has its preferred meaning and all other substituents have    their basic meaning; or-   iv) R3 has its preferred meaning and R1, R2, R4 to R8, X, Ar,    heteroaryl, heterocyclyl and aryl have their basic meaning; or-   v) R4 and R5 each have their preferred meaning and all other    substituents have their basic meaning; or-   vi) R6 has its preferred meaning and all other substituents have    their basic meaning; or-   vii) R7 has its preferred meaning and all other substituents have    their basic meaning; or-   viii) R9 has its preferred meaning and all other substituents have    their basic meaning; or-   ix) X has its preferred meaning and all other substituents have    their basic meaning; or-   x) Ar has its preferred meaning and all other substituents have    their basic meaning; or-   xi) aryl has its preferred meaning and all other substituents have    their basic meaning; or-   xii) heteroaryl has its preferred meaning and all other substituents    have their basic meaning; or-   xiii) heterocyclyl has its preferred meaning and all other    substituents have their basic meaning; or-   xiv) aryl, heterocyclyl and heteroaryl each have their preferred    meaning and all other substituents have their basic meaning; or-   xv) R4 to R7 and R9 each have their preferred meaning and all other    substituents have their basic meaning; or-   xvi) R6 and Ar each have their more preferred meaning and R1 to R5,    R7, X, heteroaryl and heterocyclyl each have their preferred    meaning; or-   xvii) R1 and 2 each have their particularly preferred meaning, Ar    has its much more preferred meaning, R3, R4, R6 and heteroaryl each    have their more preferred meaning and R7, X and heterocyclyl each    have their preferred meaning; or-   xviii) R1, R2, R7 and X each have their particularly preferred    meaning and R3, R4 and Ar each have their much more preferred    meaning; or-   xix) R1 to R4 and X each have their particularly preferred meaning    and Ar has its even much more preferred meaning; or-   xx) R1 to R4, X and Ar each have their particularly preferred    meaning; or-   xxi) R1 to R3, X and Ar each have their particularly preferred    meaning and R4 has its much more preferred meaning; or-   xxii) R1, R2 and X each have their preferred meaning, R4 has its    more preferred meaning, Ar has its even much more preferred meaning    and R3, heteroaryl and heterocyclyl each have their particularly    preferred meaning; or-   xxiii) R1, R2, X, heteroaryl and heterocyclyl each have their    particularly preferred meaning, R4 and Ar each have their more    preferred meaning, R3 has its much more preferred meaning and R7 has    its preferred meaning; or-   xxiv) R1, R2 and R7 each have their particularly preferred meaning,    R3 has its much more preferred meaning, R4, R6, Ar and heteroaryl    each have their more preferred meaning and X and heterocyclyl each    have their preferred meaning; or-   xxv) R1, R2 and Ar each have their particularly preferred meaning,    R3, R7, X and heterocyclyl each have their preferred meaning and R4,    R6 and heteroaryl each have their more preferred meaning; or-   xxvi) R1, R2, R4, R5, R7, X, heteroaryl and heterocyclyl each have    their preferred meaning, Ar has its much more preferred meaning, R6    has its more preferred meaning and R3 and R9 have their basic    meaning; or-   xxvii) R1, R2, X, Ar, heteroaryl and heterocyclyl each have their    preferred meaning, R3, R4 and R6 each have their more preferred    meaning and R7 has its particularly preferred meaning; or-   xxviii) R1 to R7, X, heteroaryl, heterocyclyl and aryl each have    their preferred meaning and Ar has its basic meaning; or-   xxix) R1, R2, X, heteroaryl, heterocyclyl and aryl each have their    preferred meaning, R3, R4 and R6 each have their more preferred    meaning, R7 has its particularly preferred meaning and Ar has its    basic meaning; or-   xxx) R1, R2, R4 to R7, R9, X, heteroaryl and heterocyclyl each have    their preferred meaning, Ar has its more preferred meaning and R3    has its basic meaning; or-   xxxi) R1, R2, R9, X, heteroaryl and heterocyclyl each have their    preferred meaning, R4, R6 and Ar each have their more preferred    meaning, R7 has its particularly preferred meaning and R3 has its    basic meaning; or-   xxxii) R3 to R7, Ar, heteroaryl and heterocyclyl each have their    preferred meaning and R1, R2 and X each have their basic meaning; or-   xxxiii) Ar has its much more preferred meaning, X, aryl, heteroaryl    and heterocyclyl each have their preferred meaning and all other    substituents have their basic meaning; or-   xxxiv) X, aryl, heteroaryl and heterocyclyl each have their    preferred meaning, R3, R4 and R6 each have their more preferred    meaning, R7 has its particularly preferred meaning and R1, R2 and Ar    each have their basic meaning.

As stated above, the preferred compounds of the general formula (I) arenot confined to the aforementioned examples. On the contrary, allcombinations of the individual substituents in their basic meaning withthe preferred, more preferred, much more preferred, even much morepreferred or particularly preferred meanings of the other substituentsor all combinations of the preferred, more preferred, much morepreferred, even much more preferred or particularly preferred meaningsof the individual substituents which are not detailed above as exampleare also an aspect of this invention. This of course applies only as faras the definitions of the respective substituents permits such acombination.

Most preferred compounds according to the general formula (I) areselected from the group consisting of:

-   4-(3-methanesulfonylphenylamino)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-(3-acetylphenylamino)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-(5-butylaminomethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   3-methyl-4-(5-pyrrolidin-1-ylmethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-[5-(3-hydroxypyrrolidin-1-ylmethyl)furan-2-yl]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-(5-{[(4-pyrrolidin-1-ylpiperidin-1-ylmethyl)amino]methyl}furan-2-yl)-5,    6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-{5-[(2-dimethylaminoethylamino)methyl]furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-{5-[(2-hydroxy-2-phenylethylamino)methyl]furan-2-yl}-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-(5-{[(4-methylpiperazin-1-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-(5-{[(1-methyl-1H-pyrazol-4-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,-   4-(5-butylaminomethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one    and-   4-(5-hydroxymethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one.

The compounds of the formula I can be prepared by various chemicalmethods which likewise belong to the present invention. Some typicalroutes are outlined in the reaction sequences referred to below asschemes 1 to 3. Substituents R are in each case defined as indicatedabove unless indicated otherwise hereinafter. The starting compounds andthe intermediate compounds (intermediates) are either commerciallyavailable or can be prepared by methods known to the skilled worker.

Intermediate II can be obtained by heating phthalic anhydride with aminoacid esters. Subsequent treatment of the phthalimides II with sodiummethanolate in methanol under reflux affords intermediates III which areconverted after reductive dehydroxylation with red phosphorus inhydroiodic acid into the isoquinolinones IV. Partial hydrogenation ofthese intermediates, some of which are also commercially available (e.g.for R1=H) or can be prepared by another route, affords thetetrahydroisoquinolinones V. Intermediate VI can be prepared therefromby bromination (which can be carried out for example withN-bromosuccinimide in methanol or with bromine in chloroform as solvent)and subsequent O-alkylation (e.g. by methyl iodide in chloroform withthe addition of silver carbonate). Intermediate VII can be prepared fromthe halide VI by palladium-catalyzed borylation (e.g. by reaction with4,4,5,5-tetramethyl-1,3,2-dioxaborolane with palladium dichloride1,1′-bis(diphenylphosphino)ferrocene as catalyst and triethylamine asbase in 1,4-dioxane as solvent). Both intermediates VI and VII aresuitable for further reaction to give the compounds I (see schemes 2 and3). The radical R2 can where appropriate be modified during or followingany reaction step in schemes 1 to 3 by means known to the skilledworker.

Compounds of the formula VIII with X equal to NH or N(C₁-C₃-alkyl) canbe prepared by Hartwig-Buchwald amination with aromatic amines catalyzedby palladium (for example with palladium dibenzylideneacetone andbis(tert-butyl)biphenylphosphine as catalyst and sodium tert-butanolateor potassium tert-butanolate as base in toluene). Compounds of theformula VIII with X=O, S can be prepared by reacting sodium or potassiumphenolates, or sodium or potassium thiophenolates, with copper catalysis(for example copper(I) chloride, copper(I) oxide or copper powder inhigh-boiling solvents such as DMF or collidine). Elimination of themethyl group from the compounds of the formula VIII (e.g. bytrimethylchlorosilane and potassium iodide in acetonitrile) affordscompounds of the formula Ia. (scheme 2). It is possible in this case forthe heteroaryl/aryl fragment (Ar) to be either unsubstituted (R′=H) orat least monosubstituted, where the substituents may be those listed inthe basic meaning of Ar (such as R′=R³ or heteroaryl) or else R′=COOH.When suitable functional groups are present, for example when R′ is acarboxylate function, further compounds of the formula Ia in which R3 is—C(O)NR4R5 can be prepared by forming an amide linkage with couplingreagents such asO-[(ethoxycarbonyl)-cyanomethyleneamino]-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TOTU).

Compounds of the formula X can be prepared by palladium-catalyzed Suzukicoupling of an aromatic boronic acid or of a boronic ester and of theintermediates VI (scheme 3). Preparation of compounds of the formula Xmay also start from intermediate VII which is coupled bypalladium-catalyzed Suzuki coupling (e.g. with palladium dichloride1,1′-bis(diphenylphosphino)ferrocene as catalyst and potassium carbonateas base in dimethylformamide) with aromatic halides (e.g. Br—Ar—R″; R″may in this case be for example hydrogen, —CHO or —COOH) (scheme 3).

-   -   for R″ CHO    -   NaCNBH₃, or MP triacetoxyborohydride, HNR4R5    -   or    -   NaBH₄    -   or    -   1. NaCNBH₃, NH₄OAc. 2. R6COCl or R6SO2Cl, pyridine for R″=COOH    -   HNR(3)R(4), TFFH or PPA

Elimination of the methyl group from the compounds of the formula X(e.g. by trimethylchlorosilane and potassium iodide in acetonitrile)affords tetrahydroisoquinolinones of the formula Xi. Compounds of theformula Ib in which R3 is —CH2NR4R5 are prepared by employing compoundsXi with R″=—CHO, which are reacted by reductive amination with aminesNR4R5. It is possible in this case to use reducing agents such as sodiumcyanoborohydride or solid phase-bound triacetoxyborohydride.

Compounds of the formula Ib in which R3 is —CH₂OH are prepared byemploying compounds XI with R″=—CHO, which are reacted by reduction forexample with sodium borohydride.

Compounds of the formula Ib in which R3 is —CH₂NHC(O)R6 or —CH₂NHSO₂R6are prepared by firstly carrying out a reductive amination with ammoniumacetate, and coupling the aminomethyl compounds obtained in this waywith appropriate acid chlorides or acids or with sulfonyl chlorides.

Compounds of the formula Ib in which R3 is —C(O)NR4R5 are prepared byemploying compounds of the formula Xi with R″=—COOH, which are coupledwith amines HNR4R5. It is possible in this case to use various suitablecondensing agents such as carbodiimides, TFFH or phosphonic anhydrides(e.g. PPA).

Compounds of the formula Ib in which R3 is —CHNOR9 are prepared byemploying compounds XI with R″=—CHO, which are reacted to form oximeswith hydroxylamines R9ONH₂.

Compounds of the formula Ib in which R3 is —SO₂NR4R5 are prepared byemploying compounds XI with R″=H, which are converted bychlorosulfonation (for example with chlorosulfonic acid and phosphoruspentachloride in chloroform) into the corresponding sulfochlorides, andthe latter are then reacted with amines HNR4R5.

Compounds of the formula Ib in which R3 is —C(O)R6 are prepared byemploying compounds Xi with R″=H, which are lithiated and then reactedwith Weinreb amides R5C(O)NMe(OMe) to give the desired compounds.

Compounds of the formula Ib in which R3 is —CH(OH)R7 are prepared bylithiating compounds Xi with R″=H and then reacting with aldehydesR7CHO.

Compounds of the formula Ib in which R3 is —NHSO₂R6 are prepared byemploying compounds XI with R″=—NH₂, which are reacted with sulfonylchlorides R6SO₂Cl in the presence of a base.

Compounds of the formula Ib in which R3 is —NHC(O)R6 are prepared byemploying compounds of the formula XI with R″=—NH₂, which are reactedwith a suitable acid chloride in the presence of a base or with asuitable acid in the presence of a condensing agent.

Compounds of the formula Ib in which R3 is —(C₂-C₃-alkyl)-NR4R5 areprepared by employing compounds XI with R″=—CHO, which are reacted witha suitable Wittig reagent, with subsequent removal of protective groupsand reductive amination of the aldehyde resulting therefrom with asuitable amine. The Wittig reagent is preferably Ph₃P═CHOR.

Compounds of the formula Ib in which R3 is —(C₂-C₃-alkyl)-NHC(O)R6 or—(C₂-C₃-alkyl)-NHSO₂R6 are prepared by employing compounds Xi withR″=—CHO, which are reacted with a suitable Wittig reagent, withsubsequent removal of the protective groups and reductive amination ofthe aldehyde with ammonium acetate to give the amine. This amine isreacted with a suitable acid chloride R6C(O)Cl or with a suitablesulfonyl chloride R6SO₂Cl in the presence of a base to give theabove-mentioned compounds.

It may be appropriate in all procedures for functional groups in themolecule to be protected temporarily in certain reaction protocols. Suchprotective groups are familiar to the skilled worker. Selection of aprotective group for groups which come into consideration, and themethods for their introduction and elimination, are described in theliterature and can be adapted where appropriate to the individual casewithout difficulties.

The present invention also relates to the use of compounds according togeneral formula (I) as pharmaceutical or medicament. Concerning thedefinitions of the substituents X, Ar, R¹ and R² (and of the othersubstituents defined via the aforementioned substituents), reference ismade to the statements concerning the compounds as such.

The use of compounds according to general formula (I) aspharmaceuticals, where one, more than one or all of the aforementionedsubstituents have the preferred, more preferred, much more preferred,even much more preferred or particularly preferred meaning mentionedabove, including all combinations with one another, is likewise anaspect of the present invention.

The compounds of the general formula (I) are PARP inhibitors and areaccordingly suitable for the treatment of diseases which are related toPARP, are promoted thereby or result from its involvement.

Examples of diseases which can be treated with the compounds accordingto the present invention include: tissue damage resulting from celldamage or cell death owing to necrosis or apoptosis, neuronally mediatedtissue damage or disorders, cerebral ischemia, head trauma, stroke,reperfusion damage, neurological disturbances and neurodegenerativedisorders, vascular stroke, cardiovascular disorders, myocardialinfarction, myocardial ischemia, experimental allergic encephalomyelitis(EAE), multiple sclerosis (MS), ischemia related to heart surgery,age-related macular degeneration, arthritis, arteriosclerosis, cancer,degenerative disorders of the skeletal muscles with subsequentreplicative senescence, diabetes and diabetic myocardial disorders.

The compounds of the present invention are preferably employed for thetreatment of diseases which are caused by ischemia or reperfusiondamage. Diseases which can be treated are more preferably selected fromthe group consisting of: cerebral ischemia, reperfusion damage,cardiovascular disorders, myocardial infarction, myocardial ischemia andischemia related to heart surgery.

The compounds of the present invention can be used in particular for thetreatment of a myocardial infarction.

The term treatment in the above statements also includes theprophylaxis, therapy or cure of the aforementioned diseases.

All references to “compound(s) according to formula (I)” hereinafterrefer to compound(s) of the formula (I) as described above, and theirsalts, solvates and physiologically functional derivatives as describedherein.

The compounds according to formula (I) can be administered to animalsand humans, preferably mammals and humans, particularly preferablyhumans. The compounds according to formula (I) can in this connection beadministered themselves as pharmaceutical, in mixtures with one anotheror in mixtures with other pharmaceuticals or in the form ofpharmaceutical compositions. Consequently, the use of compoundsaccording to formula (I) for producing one or more medicaments for theprophylaxis and/or treatment of the aforementioned diseases,pharmaceutical compositions comprising an effective amount of at leastone compound according to formula (I), and pharmaceutical compositionscomprising an effective amount of at least one compound according toformula (I) for the prophylaxis and/or treatment of the aforementioneddiseases are likewise aspects of the present invention.

The amount of a compound according to formula (I) which is necessary inorder to achieve the desired biological effect depends on a number offactors, e.g. the specific compound chosen, the intended use, the modeof administration and the clinical condition of the patient. The dailydose is generally in the range from 0.3 mg to 100 mg (typically from 3mg to 50 mg) per day per kilogram of body weight, e.g. 3-10 mg/kg/day.An intravenous dose may be for example in the range from 0.3 mg to 1.0mg/kg, which can suitably be administered as infusion of from 10 ng to100 ng per kilogram per minute. Suitable infusion solutions for thesepurposes may comprise for example from 0.1 ng to 10 mg, typically from 1ng to 10 mg, per milliliter.

Single doses may comprise for example from 1 mg to 10 g of the activeingredient. Thus, ampules for injections may comprise for example from 1mg to 100 mg, and single-dose formulations which can be administeredorally, such as, for example, tablets or capsules, may comprise forexample from 1.0 to 1000 mg, typically from 10 to 600 mg. In the case ofpharmaceutically acceptable salts, the aforementioned weight data referto the weight of the free compound from which the salt is derived. Forthe prophylaxis or therapy of the abovementioned conditions it ispossible for the compounds of the formula (I) to be used themselves ascompound, but they are preferably present together with an acceptablecarrier in the form of a pharmaceutical composition. The carrier must,of course, be acceptable in the sense that it is compatible with theother ingredients of the composition and is not harmful for thepatient's health (physiologically acceptable). The carrier may be asolid or a liquid or both and is preferably formulated with the compoundas single dose, for example as tablet which may comprise from 0.05% to95% by weight of the active ingredient. Further pharmaceutically activesubstances may likewise be present, including further compounds of theformula (I). The pharmaceutical compositions of the invention can beproduced by one of the known pharmaceutical methods, which essentiallyconsist of mixing the ingredients with pharmacologically acceptablecarriers and/or excipients.

Besides at least one compound according to formula (I) and one or morecarriers, the pharmaceutical compositions of the invention may alsocomprise excipients. Examples of suitable excipients or additives are:fillers, binders, lubricants, wetting agents, stabilizers, emulsifiers,dispersants, preservatives, sweeteners, colorants, flavorings,aromatizing substances, thickeners, diluents, buffer substances,solvents, solubilizers, agents with which a depot effect can beachieved, salts to alter the osmotic pressure, coating agents orantioxidants.

The pharmaceutical compositions of the invention may for example be inthe form of a pill, tablet, coated tablet, suckable tablet, granules,capsule, hard or soft gelatin capsule, aqueous solution, alcoholicsolution, oily solution, syrup, emulsion, suspension, suppository,pastille, solution for injection or infusion, ointment, tincture, cream,lotion, dusting powder, spray, transdermal therapeutic system, nasalspray, aerosol, aerosol mixture, microcapsule, implant, rod or patch.

Pharmaceutical compositions of the invention are those suitable fororal, rectal, topical, peroral (for example sublingual) and parenteral(e.g. subcutaneous, intramuscular, intradermal or intravenous)administration, although the most suitable mode of administrationdepends in each individual case on the nature and severity of thecondition to be treated and on the nature of the compound of formula (I)used in each case. Coated formulations and coated slow-releaseformulations also belong within the framework of the invention.Preference is given to acid- and gastric juice-resistant formulations.Suitable coatings resistant to gastric juice comprise cellulose acetatephthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulosephthalate and anionic polymers of methacrylic acid and methylmethacrylate.

Suitable pharmaceutical compounds for oral administration may be in theform of separate units such as, for example, capsules, cachets, suckabletablets or tablets, each of which contain a defined amount of thecompound according to formula (I); in the form of powders (gelatincapsules or sachets) or granules; as solution or suspension in anaqueous or nonaqueous liquid; or in the form of an oil-in-water orwater-in-oil emulsion. These compositions may, as already mentioned, beprepared by any suitable pharmaceutical method which includes a step inwhich the active ingredient and the carrier (which may consist of one ormore additional ingredients) are brought into contact. The compositionsare generally produced by uniform and homogeneous mixing of the activeingredient with a liquid and/or finely divided solid carrier, afterwhich the product is shaped if necessary. Thus, for example, a tabletcan be produced by compressing or molding a powder or granules of thecompound, where appropriate with one or more additional ingredients.Compressed tablets can be produced by tableting the compound infree-flowing form such as, for example, a powder or granules, whereappropriate mixed with a binder, lubricant, inert diluent and/or one (ormore) surface-active/dispersing agent(s) in a suitable machine. Moldedtablets can be produced by molding the compound, which is in powder formand is moistened with an inert liquid diluent, in a suitable machine.Examples of suitable diluents are starch, cellulose, sucrose, lactose orsilica gel. The pharmaceutical compositions of the invention mayadditionally comprise substances which are not diluents, for example oneor more lubricants such as magnesium stearate or talc, a colorant, acoating (coated tablets) or a lacquer.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration comprise suckable tablets which contain a compoundaccording to formula (I) with a flavoring, normally sucrose and gumarabic or tragacanth, and pastilles which comprise the compound in aninert base such as gelatin and glycerol or sucrose and gum arabic.

Pharmaceutical compositions suitable for parenteral administrationcomprise preferably sterile aqueous preparations of a compound accordingto formula (I), which are preferably isotonic with the blood of theintended recipient. These preparations are preferably administeredintravenously, although administration can also take place bysubcutaneous, intramuscular or intradermal injection. These preparationscan preferably be produced by mixing the compound with water, and makingthe resulting solution sterile and isotonic with blood. Injectablecompositions of the invention generally comprise from 0.1 to 5% byweight of the active compound.

The sterile compositions for parenteral administration may preferably beaqueous or nonaqueous solutions, suspensions or emulsions. Solvents orvehicles which can be used are water, propylene glycol, polyethyleneglycol and vegetable oils, especially olive oil, organic esters forinjection, for example ethyl oleate, or other suitable organic solvents.These compositions may also comprise adjuvants, especially wettingagents, agents for adjusting isotonicity, emulsifiers, dispersants andstabilizers. Sterilization can take place in several ways, for exampleby aseptic filtration, by introducing sterilizing agents into thecomposition, by irradiation or by heating. The compositions may also beproduced in the form of sterile solid compositions which on use aredissolved in sterile water or another sterile injection medium.

Pharmaceutical compositions suitable for rectal administration arepreferably in the form of single-dose suppositories. These can beproduced by mixing a compound according to formula (I) with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Pharmaceutical compositions suitable for topical use on the skin arepreferably in the form of ointment, cream, lotion, paste, spray, aerosolor oil. Carriers which can be used are petrolatum, lanolin, polyethyleneglycols, alcohols and combinations of two or more of these substances.The active ingredient is generally present in a concentration of from0.1 to 15% by weight of the composition, for example from 0.5 to 2%.

Transdermal administration is also possible. Pharmaceutical compositionssuitable for transdermal uses can be in the form of single patches whichare suitable for long-term close contact with the patient's epidermis.Such patches suitably contain the active ingredient in an optionallybuffered aqueous solution, dissolved and/or dispersed in an adhesive ordispersed in a polymer. A suitable active ingredient concentration isabout 1% to 35%, preferably about 3% to 15%. A particular possibility isfor the active ingredient to be released by electrotransport oriontophoresis as described for example in Pharmaceutical Research, 2(6):318 (1986).

The invention further relates to intermediates of compounds according togeneral formula (I). Intermediates according to general formula (XI)obtainable by the methods described above are also an aspect of thepresent invention. The intermediates (XI) are important especially whenthe linker X in compounds of the formula (I) is a single bond, and thesubstituent Ar is at least monosubstituted by R3.

where

-   R1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF₃ or    C₁-C₃-alkyl which is optionally substituted by hydroxy, chlorine,    methoxy or one, two or three fluorine atoms;-   R2 is hydrogen, fluorine, —CN, hydroxy, methoxy, —OCF₃, —NH₂,    —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂ or C₁-C₃-alkyl which is    optionally substituted by hydroxy, chlorine, methoxy or one, two or    three fluorine atoms;-   R8 is C₁-C₃-alkoxy, —O-phenyl, C₁-C₃-alkyl, —NH₂, —NH(C₁-C₃-alkyl),    —N(C₁-C₃-alkyl)₂ or phenyl,    -   and the above phenyl fragments may in turn be at least        monosubstituted by fluorine, chlorine, bromine, oxo, —CF₃,        —OCF₃, —NO₂, —CN, aryl, heteroaryl, —NHC(O)(C₁-C₃-alkyl), —COOH,        hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂,        —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂,        —C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl),        —NH₂, —NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂;-   Ar is aryl or heteroaryl,    -   where this aryl or heteroaryl is optionally substituted by at        least one substituent are selected from the group consisting of:        fluorine, chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8,        —NH₂, —NHC(O)(C₁-C₆-alkyl), hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy,        —CH₂—CH₂—CH₂, —CH₂—O—C(O)—, —CH₂—C(O)—O—, —CH₂—NH—C(O)—,        —CH₂—N(CH₃)—C(O)—, —CH₂C(O)—NH—, —NH(C₁-C₆-alkyl),        —N(C₁-C₆-alkyl)₂, —SO₂(C₁-C₆-alkyl), heterocyclyl, heteroaryl        and aryl,    -   and, of these substituents, heterocyclyl, aryl and heteroaryl        may in turn be at least monosubstituted by C₁-C₆-alkyl,        C₁-C₆-alkoxy, fluorine, chlorine, bromine, trifluoromethyl,        trifluoromethoxy or OH;-   R″ is —COOH, —CHO or —SO₂Cl;-   heteroaryl is a 5 to 10-membered, aromatic, mono- or bicyclic    heterocycle which comprises one or more heteroatoms selected from N,    O and S;-   heterocyclyl is a 5 to 10-membered, nonaromatic, mono- or bicyclic    heterocycle which comprises one or more heteroatoms selected from N,    O and S;-   aryl is a 5 to 10-membered, aromatic mono- or bicycle.

Preferred compounds of the formula (XI) are those in which:

-   R1 is hydrogen or C₁-C₃-alkyl;-   R2 is hydrogen;-   Ar is phenyl, thienyl, furanyl or pyridinyl,    -   where this phenyl, thienyl, furanyl or pyridinyl is optionally        substituted by at least one substituent are selected from the        group consisting of: fluorine, chlorine, —CF₃, —OCF₃,        —C(O)(C₁-C₃-alkyl), —NH₂, —NHC(O)(C₁-C₃-alkyl), hydroxy,        C₁-C₃-alkyl, C₁-C₃-alkoxy, —CH₂—CH₂—CH₂—, —CH₂—O—C(O)—,        —CH₂—C(O)—O—, —CH₂NH—C(O)—, —CH₂N(CH₃)—C(O)—, —CH₂—C(O)—NH—,        —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂ and —SO₂(C₁-C₃-alkyl);-   R″ is —COOH, —CHO or —SO₂Cl;

Particularly preferred compounds of the formula (XI) are those in which

-   R1 is hydrogen or C₁-C₃-alkyl;-   R2 is hydrogen;-   Ar is phenyl, furanyl, thienyl or pyridinyl, where R″ and the    tetrahydroquinolinone fragment are in the meta position relative to    one another;-   R″ is —CHO or —COOH.    Experimental Section

List of abbreviations ^(t)Bu tert-butyl dba dibenzylideneacetone DCMdichloromethane DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamideD6-DMSO deuterated dimethyl sulfoxide eq. mole equivalent MP highlycrosslinked macroporous polystyrene NBS N-bromosuccinimide PdCl₂(dppf)1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride PPApropanephosphonic anhydride RF reflux RT room temperature RP-HPLCreverse phase high performance chromatography SCX cation exchanger(′strong cation exchanger′) TFFH tetramethylfluoroamindiniumhexafluorophosphate TFA trifluoroacetic acid TFH tetrahydrofuran TMStrimethylsilyl TOTU O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N′,N′-tetramethyluronium tetrafluoroborateSynthesis of the Phthalimides of the Formula II

The synthesis according to scheme 1 is demonstrated by means of compound1:

Ethyl 2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)propionate (Compound 1)

20.87 g (0.141 mol) of phthalic anhydride together with 16.5 g (0.141mol) of ethyl aminopropionate in an open round-bottom flask at 120° C.for 5 h. 300 ml of cyclohexane are added, and the mixture is heated toreflux. The hot cyclohexane solution is decanted off from the remainingoil and completely concentrated. A slowly solidifying viscous oil isobtained (31 g, 89% yield).

MS: m/z=248 (M+1)

1H-NMR (CDCl3): δ=7.87 (2H, m); 7.74 (2H, m); 4.96 (1H, q, J=7.3 Hz);4.21 (2H, m); 1.70 (3H, d, J=7.3 Hz); 1.24 (3H, t, J=7.1 Hz).

4-Hydroxy-3-methyl-2H-isoquinolin-1-one (Compound 2)

31.8 g (129 mmol) of compound 1 are dissolved in 22 ml of absolutemethanol and, after addition of 15.2 ml of 28% sodium methanolatesolution (257 mmol), heated to reflux for 3 h. The solution isconcentrated and conc. aqueous ammonia solution is added to the residue.After 2 h, the solid is filtered off with suction and washed with coldwater. 14.1 g (63% yield) of white solid are obtained.

MS: m/z=176 (M+1)

1H-NMR (CD3OD): δ=8.21 (1H, d, J=8.8 Hz); 8.14 (1H, d, J=8.3 Hz); 7.65(1H, m); 7.38 (1H, m); 2.30 (3H, s).

3-Methyl-2H-isoquinolin-1-one (Compound 3)

24.6 g (140 mmol) of 4-hydroxy-3-methyl-2H-isoquinolin-1-one are heatedtogether with 9.13 g (294 mmol) of red phosphorus in 55% hydriodic acid(130 ml) at 160° C. for 7 days. The cooled mixture is poured into waterand extracted with dichloromethane. 10.2 g (46% yield) of a white solidare obtained.

MS: m/z=160 (M+1)

1H-NMR (CDCl23): δ 10.55 (1H, s); 8.37 (1H, d, J=8.1 Hz); 7.62 (1H, m);7.43 (2H, m); 6.31 (1H, s); 2.37 (3H, s).

3-Methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 4)

8.45 g (53 mmol) of 3-methyl-2H-isoquinolin-1-one are dissolved in 80 mlof glacial acetic acid and, after addition of 168 mg (0.74 mmol) ofplatinum(IV) oxide, hydrogenated under 5 bar at RT for 8 h. Thesuspension is filtered and concentrated and the residue isrecrystallized from methanol. 7.15 g (83%) of a colorless oil areobtained.

MS: m/z=164 (M+1)

1H-NMR (CDCl3): δ 10.7 (1H, s); 5.78 (1H, s); 2.50 (4H, m); 2.22 (3H,s); 1.73 (4H, m).

5,6,7,8-Tetrahydro-2H-isoquinolin-1-one (compound 5)

60 g (413 mmol) of 2H-isoquinolin-1-one (=isocarbostyril) are dissolvedin 1 l of glacial acetic acid and, after addition of 2.3 g (10 mmol) ofplatinum(IV) oxide, hydrogenated under 3 bar at RT until conversion iscomplete. This entailed changing the catalyst after 3 days and a further5 days. The suspension is filtered, concentrated and again concentratedafter addition of toluene. The crude product is recrystallized from 1.6l of water. Long needles are filtered off, and the mother liquor isconcentrated and dried and separated on silica gel. 36.8 g (60%) of acolorless oil are obtained.

MS: m/z=150 (M+1)

1H-NMR (D6-DMSO): δ=11.20 (1H, s); 7.08 (1H, d, J=6.8 Hz); 5.90 (1H, d,J=6.8 Hz); 2.47 (2H, m); 2.30 (2H, m); 1.64 (4H, m).

4-Bromo-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 6)

7.15 g (43.8 mmol) of compound 4 are dissolved in 50 ml of methanol at0° C., and a total of 7.4 g (41.6 mmol) of N-bromosuccinimide is addedin portions. After a reaction time of 3 h at 0°, the residue fromfiltration with suction is washed with a little cold water anddichloromethane. 8.9 g (84% yield) of the colorless bromide areobtained.

MS: m/z=242/244 (M+1)

1H-NMR (CDCl3): δ=12.4 (1H, s); 2.57 (4H, m); 2.43 (3H, s); 1.75 (4H,m).

4-Bromo-5,6,7,8-tetrahydro-2H-isoquinolin-1-one (Compound 7)

32.4 g (217 mmol) of tetrahydroisoquinolinone (compound 5) is dissolvedin 300 ml of chloroform at 5° C. and then 11.2 ml (34.7 g, 217 mmol) ofbromine, dissolved in 150 ml of chloroform, are added dropwise over thecourse of 1 h. The mixture is stirred while cooling in ice for a furtherhour and then neutralized with 150 ml of saturated NaHCO3 solution andfiltered with suction. The organic phase of the filtrate is extractedwith dichloromethane and concentrated. The residue is mixed with ethylacetate, filtered off with suction and dried together with the firstresidue in a vacuum drying oven at 45° C. 47.7 g (96%) of colorlessbromide are obtained.

MS: m/z=228/230 (M+1)

1H-NMR (CDCl3): δ=9.50 (1H, s); 8.03 (1H, s); 2.28 (2H, m); 2.18 (2H,m); 1.85 (4H, m).

4-Bromo-1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinoline (Compound 8)

8.9 g (36.8 mmol) of4-bromo-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one are dissolvedin 200 ml of chloroform and, after addition of 13.7 g (49.6 mmol) ofsilver(I) carbonate and 16.2 ml (36.5 g, 257 mmol) of methyl iodide,stirred at 50° C. for 3 h. After a further 24 h at RT, the suspension isfiltered through Celite, concentrated and chromatographed on silica gelusing n-heptane with addition of 2% ethyl acetate. A colorless oil (7.8g, 83% yield) is obtained.

MS: m/z=256/258 (M+1)

1H-NMR (CDCl3): δ=3.89 (3H, s), 2.65 (2H, m); 2.53 (2H, m); 2.51 (3H,s); 1.75 (4H, m).

4-Bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline (Compound 9)

47.7 g (209 mmol) of 4-bromo-5,6,7,8-tetrahydro-2H-isoquinolin-1-one aredissolved in 1 l of chloroform and, after addition of 77.8 g (282 mmol)of silver(I) carbonate and 53.5 ml (118.7 g, 836 mmol) of methyl iodide,stirred at 50° C. for 3 h. After cooling, the suspension is filteredthrough Celite, concentrated and chromatographed on silica gel usingn-heptane with addition of 2% ethyl acetate. A colorless oil (42.5 g,84% yield) is obtained.

MS: m/z=242/244 (M+1)

1H-NMR (CDCl3): δ=8.03 (1H, s); 3.90 (3H, s); 2.66 (2H, m); 2.57 (2H,m); 1.78 (4H, m).

1-Methoxy-3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,6,7,8-tetrahydroisoquinoline (Compound 10)

128 mg (0.5 mmol) of the bromide 8, 218 μl (1.64 mmol) of triethylamineand 83 mg (0.65 mmol) of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane aredissolved in 2 ml of dioxane under argon, finally 19 mg (0.027 mmol) ofPdCl2(dppf) are added, and the mixture is stirred at 90° C. for 60 h andthen for a further 2.5 h at 150° C. in a microwave. The mixture isdiluted with water and ethyl acetate, and the organic phase is washedwith water, concentrated and purified on silica gel. A white solid (100mg, 66% yield) is obtained.

MS: m/z=304 (M+1)

1H-NMR (CDCl3): δ=4.08 (3H, s); 2.68 (2H, m); 2.58 (3H, s); 2.52 (2H,m); 1.75 (4H, m); 1.38 (12H, s).

1-Methoxy-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-5,6,7,8-tetrahydroisoquinoline(Compound 11)

8.0 g (33 mol) of the bromide 9, 14.4 ml (109 mmol) of triethylamine and5.5 g (42.9 mmol) of 4,4,5,5-tetramethyl-1,3,2-dioxaborolane aredissolved in 50 ml of dioxane under argon, finally 1.28 g (1.75 mmol) ofPdCl2(dppf) are added, and the mixture is stirred at 90° C. for 18 h.The cooled mixture is mixed with water and extracted twice with ethylacetate, and the organic phase is dried, concentrated andchromatographed on silica gel. A white solid (7.75 g, 81% yield) isobtained.

MS: m/z=290 (M+1)

1H-NMR (CDCl3): δ=8.01 (1H, s); 4.07 (3H, s); 2.66 (2H, m); 2.51 (2H,m); 1.75 (4H, m); 1.38 (12H, s).

Hartwig-Buchwald aminations of bromides of the formula VI to givecompounds of the formula VIII.

General Procedure;

1 eq. of bromide (compound 8 or 9), 1.5 eq. of aniline and 1.4 eq. ofNaOtBu are introduced into absolute toluene (2 ml/mmol) under argon.After stirring at RT for 10 min, 0.05 eq. oftris(dibenzylideneacetone)-dipalladium and 0.2 eq. ofdi-tert-butylphosphinobiphenyl are added, and the mixture is reacted at150° C. in a microwave (CEM Discover) for 60 min. The reaction mixtureis diluted with water and ethyl acetate, and the organic phase isseparated off, concentrated and purified by RP-HPLC. Basic compounds areisolated as trifluoroacetates.

Ethyl 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino)benzoate(Compound 12)

580 mg (4.9 mmol) of 95% pure KO^(t)Bu are introduced into 20 ml of abs.toluene. After evacuation and ventilation with argon three times, 847 mg(3.5 mmol) of 4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline, and 868mg (5.25 mmol) of ethyl 3-aminobenzoate are added. Addition of 160 mg(0.175 mmol) of tris(dibenzylidene)dipalladium and 209 mg (0.7 mmol) ofdi-tert-butylphosphinobiphenyl is followed by heating at 100° C. forthree hours. For workup, the mixture is concentrated and the residue ispartitioned between H₂O and ethyl acetate. The phases are separated andthe aqueous phase is extracted three times more. The combined organicphases are washed once more with H₂O, dried with Na₂SO₄ andconcentrated. Further purification takes place by chromatography onsilica gel (CH₂Cl₂/MeOH 99:1), resulting in 640 mg of the titlecompound. Yield: 55%.

The following further compounds are prepared in accordance with thegeneral procedure:

Compound Name 13 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 271 (M + 1)4-ylamino)phenol 14 3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 312(M + 1) 4-ylamino)-N-methylbenzamide 15(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 339 (M + 1)4-yl)(4-pyridin-4-ylthiazol-2-yl)amine 16(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 339 (M + 1)4-yl)(3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-5′-yl)amine 17N-[3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 312 (M + 1)4-ylamino)phenyl]acetamide 18(3-methanesulfonylphenyl)(1-methoxy-5,6,7,8- 333 (M + 1)tetrahydroisoquinolin-4-yl)amine 19(3-methanesulfonylphenyl)(1-methoxy-3- 337 (M + 1)methyl-5,6,7,8-tetrahydroisoquinolin-4-yl)amine 20[3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 285 (M + 1)4-ylamino)phenyl]methanol 21 (6-methoxypyridin-3-yl)(1-methoxy-5,6,7,8-286 (M + 1) tetrahydroisoquinolin-4-yl)amine 226-(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 311 (M + 1)4-ylamino)-3H-isobenzofuran-1-one 23(3-ethoxyphenyl)(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 311 (M + 1)4-yl)amine 24 (6-chloropyridin-3-yl)(1-methoxy-5,6,7,8- 290 (M + 1)tetrahydroisoquinolin-4-yl)amine 253-(1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin- 340 (M + 1)4-ylamino)-N,N-dimethylbenzamide 26(1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin- 353 (M + 1)4-yl)(3-trifluoromethoxyphenyl)- amine 271-[3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin- 297 (M + 1)4-ylamino)phenyl]ethanone 281-[3-(1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin- 311 (M + 1)4-ylamino)phenyl]ethanone 29N-[3-(1-methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin- 326 (M + 1)4-ylamino)phenyl]acetamideSynthesis of Compounds of the Formula X by Suzuki Coupling with Bromidesof the Formula VI and Boronic Acids of the Formula (OH)₂B—Ar—R″General Procedure

1 eq. of bromide (compound 8 or 9), 3.3 eq. of potassium iodide, 1.2 eq.of boronic acid are introduced under argon into absolute THF (3 ml/1mmol). 0.05 eq. of Pd2dba3 and 0.1 eq. of tri-tert-butylphosphoniumtetrafluoroborate are added, and the mixture is stirred at 60° C. for 15h. After cooling, it is neutralized with saturated NaHCO3 solution andextracted twice with ethyl acetate, and the organic phase isconcentrated. The residue is chromatographed on silica gel.

1-Methoxy-3-methyl-4-thiophen-2-yl-5,6,7,8-tetrahydroisoquinoline(Compound 30)

22 mg (31% yield) of compound 30 are obtained from 70 mg of bromide 8 inaccordance with the general procedure

MS: m/z=260 (M+1)

1H-NMR (CDCl3): δ=7.37 (1H, dd, J=5.1, 1.1 Hz); 7.09 (1H, dd, J=5.1, 3.4Hz); 6.79 (1H, dd, 3.4, 1.1 Hz); 3.96 (3H, s); 2.58 (2H, m); 2.40 (2H,m); 2.24 (3H, s); 1.70 (4H, m).

1-Methoxy-3-methyl-4-pyridin-3-yl-5,6,7,8-tetrahydroisoquinoline(Compound 31)

49 mg (49% yield) of compound 31 are obtained from 100 mg of bromide 8in accordance with the general procedure.

MS: m/z=260 (M+1)

5-(1-Methoxy-5,6,7,8-tetrahydroisoquinolin-4-yl)furan-2-carbaldehyde(Compound 32)

4.59 g (100% yield) of compound 32 are obtained from 4.32 g (17.9 mmol)of bromide 9 in accordance with the general procedure.

MS: m/z=258 (M+1)

5-(1-Methoxy-3-methyl-5,6,7,8-tetrahydroisoquinolin-4-yl)furan-2-carbaldehyde(Compound 33)

1.86 g (79% yield) of compound 33 are obtained from 2.0 g of bromide 8in accordance with the general procedure.

MS: m/z=272 (M+1)

1H-NMR (CDCl3): δ=9.65 (1H, s); 7.34 (1H, d, J=3.4 Hz); 6.49 (1H, d,J=3.4 Hz); 3.96 (3H, s); 2.57 (2H, m); 2.46 (2H, m); 2.30 (3H, s); 1.71(4H, m).

Synthesis of Compounds of the Formula X by Suzuki Coupling with BoronicEsters of the Formula VII and Bromides of the Formula Br—Ar—R3

The synthesis is shown for the following compound by way of example:

5-(1-Methoxy-5,6,7,8-tetrahydroisoquinolin-4-yl)nicotinic acid (Compound34)

7.75 g (26.8 mmol) of boronic ester 11, 14.82 g (107.2 mmol) ofpotassium carbonate and 980 g (1.34 mmol) of PdCl2(dppf) are introducedinto 60 ml of absolute DMF under argon, and 7 g (34.9 mmol) of5-bromonicotinic acid are added. The mixture is stirred at 110° C. for18 h, water is added, and the pH is adjusted to 4 with 2N HCL solution.Two extractions are carried out with DCM, and the organic phase isfiltered and concentrated. The residue is taken up in 200 ml of DCM,mixed with activated carbon and filtered through Celite. The filtrate isconcentrated and dried in a vacuum drying oven overnight. 7.4 g (97%yield) of dark crystals are obtained.

MS: m/z=285 (M+1)

Synthesis of Compounds 35-39 (Intermediates) by Deprotection of theMethoxy Group:

5-(1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)furan-2-carbaldehyde(Compound 35)

4.59 g (17.8 mmol) of compound 32 are suspended in 60 ml ofacetonitrile. Addition of 3.26 g (19.6 mmol) of KI and 2.13 g (19.6mmol) of trimethylchlorosilane is followed by treatment at 60° C. underargon for 6 h. The mixture is completely concentrated and the residue istreated with aqueous NaHCO3 solution. The remaining residue is thenextracted 3× with DCM, and the organic phases are dried andconcentrated. The residue is dissolved in 100 ml of EtOH, and Noritcarbon is added. Filtration and concentration are carried out. About 1 gof the title compound is obtained. Further crude product is isolatedfrom the carbon residue by extraction with DCM and is purified on silicagel. Overall yield: 2.38 g (55%) of white solid.

MS: m/z=244 (M+1)

1H-NMR (CDCl3): δ=12.6 (1H, s); 9.65 (1H, s); 7.75 (1H, s); 7.29 (1H, d,J=3.4 Hz); 6.56 (1H, d, J=3.4 Hz); 2.75 (2H, m); 2.62 (2H, m); 2.62 (2H,m); 1.70 (4H, m).

5-(3-Methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)furan-2-carbaldehyde(Compound 36)

172 mg (27% yield) of the title compound are obtained in analogy tocompound 35 from 660 mg (2.43 mmol) of compound 33 after purification byRP-HPLC.

MS: m/z=258 (M+1)

1H-NMR (CDCl3): δ=11.4 (1H, br s); 9.65 (1H, s); 7.35 (1H, d, J=3.4 Hz);6.58 (1H, d, J=3.4 Hz); 2.61 (2H, m); 2.43 (2H, m); 2.35 (3H, s); 1.72(4H, m).

5-(1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)nicotinic acid (Compound37)

3.1 g (28.5 mmol) of compound 34 are suspended in 100 ml ofacetonitrile. Addition of 4.73 g (28.5 mmol) of KI and 3.1 g (28.5 mmol)of trimethylchlorosilane is followed by heating at 80° C. under argonfor 2 h. The mixture is cooled to RT, completely concentrated and takenup in 5:1 ethyl acetate/MeOH. The precipitate (4.78 g) is filtered offwith suction and dried in a vacuum drying oven at 45° C. overnight. Themother liquor is concentrated and the residue is purified on silica gel.Overall yield: 5.64 g (81%) of beige solid.

MS: m/z=271 (M+1)

1H-NMR (D6-DMSO): δ=11.7 (1H, br s); 9.03 (1H, d, J=2.0 Hz); 8.74 (1H,d, J=2.2 Hz); 8.12 (1H, t, J=2.2 Hz); 2.41 (2H, m); 2.32 (2H, m); 1.63(4H, m).

Ethyl 3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino)benzoate(Compound 38)

560 mg (1.7 mmol) of ethyl3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino)benzoate (compound12) are dissolved in 30 ml of chloroform and, at room temperature, 413mg (2.1 mmol) of trimethylsilyl iodide are added. The mixture is thenheated to reflux until complete conversion is reached by means of LCMS.Further trimethylsilyl iodide is added if necessary. For workup, themixture is washed twice with H₂O, dried with Na₂SO₄ and concentrated.Chromatography on silica gel (CH₂Cl₂/MeOH 95:5) affords 216 mg of thetitle compound. Yield: 40%.

MS: m/z=313 (M+1)

3-(1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino)benzoic acid(Compound 39)

180 mg (0.58 mmol) of ethyl3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino)benzoate (compound38) are introduced into 3 ml of ethanol and, at room temperature, 3 mlof 2N KOH are added. After two hours, the solvent is removed in vacuoand the residue is taken up in 5 ml of H₂O and acidified with 2N HCl.The resulting precipitate is filtered off with suction and dried. Yield:123 mg (75%).

MS: m/z=285 (M+1)

Synthesis of tetrahydro-2H-isoquinolinones of the Formula I byDeprotection of the 1-methoxy-5,6,7,8-tetrahydroisoquinolines of theFormula VIII and X.

General Procedure

2 eq. of potassium iodide and 2 eq. of trimethylchlorosilane are addedto a mixture of the 1-methoxy-5,6,7,8-tetrahydroisoquinolines of theformula VIII and IX in anhydrous acetonitrile (3-5 ml/mmol) under argon,and the turbid mixture is heated at 60-80° C. for 1-3 h. The mixture isthen cooled to RT and concentrated. The crude product is purified byRP-HPLC, basic compounds being isolated as trifluoroacetates.

The following examples are synthesized in accordance with the generalprotocol:

Mass(ES+) NMR(D6-DMSO) Example Name m/z = δ = 14-(3-hydroxyphenylamino)- 257(M + 1) 5,6,7,8-tetrahydro-2H-isoquinolin-1-one 2 N-methyl-3-(1-oxo-1,2,5,6,7,8- 298(M + 1)hexahydroisoquinolin-4-ylamino)- benzamide 3 4-(4-pyridin-4-ylthiazol-2-325(M + 1) ylamino)-5,6,7,8-tetrahydro-2H-isoquinolin- 1-one 44-(6-morpholin-4-ylpyridin-3-yl- 325(M + 1)amino)-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 5N-[3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 298(M + 1) 4-ylamino)-phenyl]acetamide 6 4-(3-methanesulfonylphenyl- 319(M + 1)amino)-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 74-(3-methanesulfonylphenyl- 333(M + 1) 11.47(1H, br s),amino)-3-methyl-5,6,7,8-tetrahydro- 7.48(1H, s), 2H-isoquinolin-1-one7.32(1H, m); 7.09(1H, d, J=8.6 Hz), 6.95(1H, br s), 6.67(1H, br s),3.13(3H, s), 2.33(4H, m), 2.01(3H, s), 1.58(4H, m) 84-(3-hydroxymethylphenyl- 271(M + 1) amino)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one

4-(5-Hydroxymethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one(Example 9)

The title compound is obtained as by-product in the reductive aminationof5-(3-methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)furan-2-carbaldehyde(compound 36) and is isolated by RP-HPLC.

MS: m/z=260 (M+1)

1H-NMR (D6-DMSO): δ=11.52 (1H, br s); 6.33 (1H, d, J=2.9 Hz); 6.27 (1H,d, J=2.9 Hz); 4.38 (2H, s); 2.33 (2H, m); 2.23 (2H, m); 2.03 (3H, s);1.59 (4H, m).

Examples 10 to 19 which follow are prepared in accordance with Examples1 to 8.

Mass (ES+) NMR(D6-DMSO) Example Name m/z = δ = 104-(3-oxo-1,3-dihydrobenzofuran- 297(M + 1)5-ylamino)-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 114-(3-ethoxyphenylamino)-5,6,7,8- 285(M + 1)tetrahydro-2H-isoquinolin-1-one 124-(6-chloropyridin-3-ylamino)-5,6,7,8- 276(M + 1)tetrahydro-2H-isoquinolin-1-one 13 N,N-dimethyl-3-(3-methyl-1-oxo-326(M + 1) 1,2,5,6,7,8-hexahydroisoquinolin- 4-ylamino)benzamide 143-methyl-4-(3-trifluoromethoxy- 339(M + 1)phenylamino)-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 154-(3-acetylphenylamino)-5,6,7,8- 283(M + 1)tetrahydro-2H-isoquinolin-1-one 16 4-(3-acetylphenylamino)-3-methyl-297(M + 1) 11.42(1H, br s), 5,6,7,8-tetrahydro-2H-isoquinolin- 7.21(2H,m), 1-one 7.18(1H, m), 6.98(1H, br s), 6.63(1H, br s), 2.48(3H, s),2.32(4H, m), 2.00(3H, s), 1.57(4H, m) 17N-[3-(3-methyl-1-oxo-1,2,5,6,7,8- 312(M + 1)hexahydroisoquinolin-4-ylamino)- phenyl]acetamide 183-methyl-4-thiophen-2-yl-5,6,7,8- 246(M + 1)tetrahydro-2H-isoquinolin-1-one 19 3-methyl-4-pyridin-3-yl-5,6,7,8-241(M + 1) tetrahydro-2H-isoquinolin-1-one

Synthesis of Examples 20-24 by Coupling Compound 39 with Amines

General Procedure

38 mg (0.13 mmol) of3-(1-methoxy-5,6,7,8-tetrahydroisoquinolin-4-ylamino)benzoic acid areintroduced into 2 ml of DMF and, at room temperature, 20 μl (0.15 mmol)of triethylamine are added. At 0° C., 52 mg (0.16 mmol) of TOTU areadded, and the mixture is stirred at 0° C. for 15 min. After a further30 minutes at room temperature, this solution is added to a secondsolution consisting of the respective amine (0.15 mmol), 20 μl (0.15mmol) of triethylamine in 2 ml of DMF, and stirred at room temperatureuntil complete conversion is found by LCMS. For workup, the solvent isremoved and purification on silica gel is carried out.

The following compounds are prepared by the indicated general procedure:

N-Butyl-3-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino)benzamide(Example 20)

Yield after silica gel chromatography (CH₂Cl₂/MeOH 95:5) 31%.R_(t)=1.166 min¹); MS(M+H⁺)=340.15; 500 MHz ¹H-NMR (DMSO-d₆)[ppm]:11.30, 1H, s, NH; 7.20-7.00, m, 5H, 4×aromat. H, NH; 6.62, dd, 1H,aromat. H, 3.20, m, 2H, CH₂; 2.33 m, 4H, 2×CH₂; 1.62, m, 2H, CH₂; 1.58,m, 2H, CH₂; 1.46, m, 2H, CH₂, 1.30, m, 2H, CH₂; 0.88, t, 3H, CH₃.

4-[3-(Pyrrolidin-1-carbonyl)phenylamino]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one(Example 21)

Yield after silica gel chromatography (CH₂Cl₂/MeOH 95:5) 74% R_(t)=1.052min¹); MS(M+H⁺)=338.15; 500 MHz ¹H-NMR (DMSO-d₆)[ppm]: 11.30, 1H, s, NH;7.22-7.05, m, 3H, 2×aromat. H, NH; 6.71, dd, 1H, aromat. H, 6.63-6.55,m, 2H, aromat. H, 3.08, m, 4H, 2×CH₂; 2.33, m, 4H, 2×CH₂; 1.90-1.73, m,4H, 2×CH₂; 1.68-1.52, m, 4H, 2×CH₂.

4-[3-(4-Cyclopropylmethylpiperazine-1-carbonyl)phenylamino]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one(Example 22)

Yield after silica gel chromatography (CH₂Cl₂/MeOH 95:5) 67%.

R_(t)=0.839 min¹); MS(M+H⁺)=407.25.

3-(1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino)-N-(2-pyridin-3-ylethyl)benzamide(Example 23)

Yield after silica gel chromatography (ethyl acetate/MeOH 10:1→4:1) 63%.

R_(t)=1.03 min²); MS(M+H⁺)=389.11.

3-(1-Oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-ylamino)-N-(2-pyrrolidin-1-ylethyl)benzamide(Example 24)

Yield after silica gel chromatography (ethyl acetate/MeOH 10:1→MeOH)66%.

R_(t)=1.05 min²); MS(M+H⁺)=381.15.

LCMS Method:

-   ¹⁾ YMC J'sphere ODS H80 20×2, 4 μm;    -   0 min 96% H₂O (0.05% TFA) 2.0 min−95% ACN; 95% ACN to 2.4 min;        4% ACN 2.45 min;    -   1 ml/min;    -   30° C.-   ²⁾ Col YMC J'sphere 33×2, 4 μm;    -   Grad ACN+0.05% TFA: H2O+0.05% TFA 5.95 (0 min) to 95:5 (3.4 min)        to 95:5 (4.4 min);    -   1 ml/min;    -   30° C.

Synthesis of Examples 25-49 by Coupling Compound 37 with Amines

General Procedure

54 mg (0.2 mmol) of5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)-nicotinic acid, 0.24mmol of amine, 0.02 mmol of 4-DMAP, 0.8 mmol of N-methylmorpholine and0.4 mmol of PPA (50% solution in DMF) are mixed in 3 ml of absolute DCMat RT and stirred for 18 h. The mixture is diluted with a little DCM andwashed with saturated NaHCO3 solution, the organic phase is thenconcentrated and the residue is purified by RP-HPLC. Basic compounds areisolated as trifluoroacetates.

The following examples are prepared in accordance with the generalprotocol:

Mass (ES+) NMR(D6-DMSO) Example Name m/z = δ = 254-[5-(pyrrolidine-1-carbonyl)- 324(M + 1)pyridin-3-yl]-5,6,7,8-tetrahydro- 2H-isoquinolin-1-one 265-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 388(M + 1) 4-yl)-N-(2-oxo-2-phenylethyl)nicotinamide 27 5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-374(M + 1) 4-yl)-N-phenethyl- nicotinamide 28N-(4-nitrobenzyl)-5-(1-oxo- 405(M + 1) 1,2,5,6,7,8-hexahydroisoquinolin-4-yl)nicotinamide 29 N-[2-(4-nitrophenyl)ethyl]-5-(1- 417(M + 1)oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 30N-[(4-nitrobenzoylamino)methyl]- 433(M + 1)5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 31N-[2-(4-pyridinecarbamoylaminoethyl)]- 418(M + 1) 5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)- nicotinamide 32N-methyl-N-(3-nitrobenzyl)-5-(1- 419(M + 1)oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 335-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 391(M + 1)4-yl)-N-[2-(pyrimidin- 2-ylamino)ethyl]nicotinamide 34N-(5-methylisoxazol-3-ylmethyl)- 365(M + 1)5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 355-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 392(M + 1) 4-yl)-N-(1,3,5-trimethyl-1H-pyrazol-4-ylmethyl)- nicotinamide 364-[5-(3-pyridin-4-ylpyrrolidine-1-carbonyl) 401(M + 1)pyridin-3-yl]-5,6,7,8-tetrahydro- 2H-isoquinolin-1-one 37N-(4-acetylaminobenzyl)-5-(1- 417(M + 1)oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 38N-methyl-5-(1-oxo-1,2,5,6,7,8- 375(M + 1) hexahydroisoquinolin-4-yl)-N-pyridin-4-ylmethylnicotinamide 39 N-(5-methylpyrazin-2-ylmethyl)-5-376(M + 1) (1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 405-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 375(M + 1)4-yl)-N-(2-pyridin-3- ylethyl)nicotinamide 415-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 429(M + 1)4-yl)-N-(3-phenyl-4,5- dihydroisoxazol-5-ylmethyl)- nicotinamide 42N-(4-methanesulfonylbenzyl)-5- 438(M + 1)(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 435-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 375(M + 1) 11.60(1H, br s),4-yl)-N-(2-pyridin-4- 8.88(1H, d, J=2.1 Hz), ylethyl)nicotinamide8.78(1H, t, J=5.5 Hz), 8.74(2H, d, J=6.2 Hz), 8.65(1H, d, J=2.1 Hz),8.03(1H, t, J=2.1 Hz), 7.80(2H, d, J=6.2 Hz), 7.18(1H, s); 3.65(2H, m),3.10(2H, t, J=6.5 Hz); 2.41(2H, m), 2.31(2H, m), 1.69(2H, m), 1.59(2H,m). 44 5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 453(M + 1)4-yl)-N-[2-(4-sulf- amoylphenyl)ethyl]nicotinamide 45N-(3-methoxybenzyl)-5-(1-oxo- 390(M + 1) 11.67(1H, br s),1,2,5,6,7,8-hexahydroisoquinolin- 9.23(1H, t, J=5.8Hz),4-yl)nicotinamide 9.00(1H, d, J=1.9 Hz), 8.67(1H, d, J=2.1 Hz), 8.18(1H,t, J=2.0 Hz), 7.25(1H, t, J=8.0 Hz), 7.20(1H, s), 6.91(2H, m); 6.82(1H,m), 4.49(2H, d, J=5.8 Hz), 3.74(3H, s), 2.41(2H, m), 2.34(2H, m),1.68(2H, m), 1.58(2H, m). 46 N-(2-methoxybenzyl)-5-(1-oxo- 390(M + 1)1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 47N-(2,3-dimethoxybenzyl)-5-(1- 420(M + 1)oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide 485-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 361(M + 1) 4-yl)-N-pyridin-4-ylmethylnicotinamide 49 N-(1-ethylpyrrolidin-2-ylmethyl)-5- 381(M + 1)(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 4-yl)nicotinamide

4-(5-Aminomethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one(Example 50)

2.18 g (9.0 mmol) of compound 35 are dissolved with 844 mg (13.4 mmol)of NaCNBH4 and 55.3 g (717 mmol) of ammonium acetate in 160 ml ofmethanol/THF (5/1) and reacted at RT for 18 h. The yellow solution iscompletely concentrated and the residue is chromatographed on silica gelwith ethyl acetate/methanol (1/1). The isolated compound, which stillcontains relatively large amounts of salt, is subsequentlychromatographed by RP-HPLC. 400 mg of the title compound are isolated.

MS: m/z=245 (M+1)

Synthesis of Examples 51-79 by Reductive Amination of Compound 35 and 36with Amines

General Procedure

0.2 mmol of5-(3-methyl-1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)furan-2-carbaldehydeor 5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin-4-yl)furan-2-carbaldehydeand 0.24 mmol of amine are dissolved in 2 ml of THF and, after additionof about 0.5 mmol of MP triacetoxyborohydrides, shaken at RT for 18 h.The solution is filtered off, the resin is washed twice with 4 ml of THFeach time, and the complete organic phase is concentrated and purifiedby RP-HPLC. The compounds are isolated as trifluoroacetates after freezedrying.

Mass (Es+) NMR(D6-DMSO) Example Name m/z = δ = 514-[5-(benzylaminomethyl)furan-2- 349(M + 1)yl]-3-methyl-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 523-methyl-4-(5-{[(1-methyl-1H- 353(M + 1)pyrazol-4-ylmethyl)amino]methyl}- furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one 53 4-(5-butylaminomethylfuran-2-yl)-3- 315(M + 1)methyl-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 543-methyl-4-(5-pyrrolidin-1- 313(M + 1) 11.62(1H, br s),ylmethylfuran-2-yl)-5,6,7,8- 10.03(1H, br s),tetrahydro-2H-isoquinolin-1-one 6.74(1H, d, J=3.4 Hz), 6.47(1H, d, J=3.4Hz), 4.46(2H, d, J=5.2 Hz), 3.40(2H, m), 3.11(2H, m), 2.34(2H, m),2.23(2H, m), 2.04(3H, s), 1.86(2H, m), 1.62(4H, m). 554-(5-{[(1-methyl-1H-benzoimidazol- 389(M + 1)2-ylmethyl)amino]methyl}furan-2-yl)- 5,6,7,8-tetrahydro-2H-isoquinolin-1-one 56 4-[5-(4-pyrimidin-2-ylpiperazin-1- 392(M + 1)ylmethyl)furan-2-yl]-5,6,7,8- tetrahydro-2H-isoquinolin-1-one 574-{5-[(2-pyrrolidin-1-ylethylamino)- 342(M + 1)methyl]furan-2-yl}-5,6,7,8- tetrahydro-2H-isoquinolin-1-one 584-(5-{[(pyridin-4-ylmethyl)amino]- 336(M + 1)methyl}furan-2-yl)-5,6,7,8- tetrahydro-2H-isoquinolin-1-one 594-(5-{[(pyridin-3-ylmethyl)amino]- 336(M + 1)methyl}furan-2-yl)-5,6,7,8-tetrahydro- 2H-isoquinolin-1-one 604-(5-{[2-(1-methylpyrrolidin-2-yl)- 356(M + 1)ethylamino]methyl}furan-2-yl)- 5,6,7,8-tetrahydro-2H-isoquinolin- 1-one61 4-(5-pyrrolidin-1-ylmethylfuran-2-yl)- 299(M + 1)5,6,7,8-tetrahydro-2H-isoquinolin- 1-one 624-(5-{[(pyridin-2-ylmethyl)amino]- 336(M + 1)methyl}furan-2-yl)-5,6,7,8- tetrahydro-2H-isoquinolin-1-one 634-[5-(3-hydroxypyrrolidin-1- 315(M + 1) ylmethyl)furan-2-yl]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one 64 4-(5-{[(4-pyrrolidin-1-ylpiperidin-1-411(M + 1) ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin- 1-one 65 4-{5-[(2-dimethylaminoethyl-316(M + 1) amino)methyl]furan-2-yl}-5,6,7,8-tetrahydro-2H-isoquinolin-1-one 66 4-(5-{[methyl-(4,5,6,7-tetrahydro-410(M + 1) benzothiazol-2-ylmethyl)amino]- methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one 67 4-[5-(2-pyridin-2-ylpyrrolidin-1-376(M + 1) ylmethyl)furan-2-yl]-5,6,7,8- tetrahydro-2H-isoquinolin-1-one68 4-(5-{[(1H-benzimidazol-2- 375(M + 1)ylmethyl)amino]methyl}furan-2-yl)- 5,6,7,8-tetrahydro-2H-isoquinolin-1-one 69 4-(5-{[benzyl(1-methyl-1H-imidazol- 429(M + 1)2-ylmethyl)amino]- methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one 70 4-[5-(indan-2-ylaminomethyl)-361(M + 1) furan-2-yl]-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 714-[5-({[4-(4-fluorophenyl)- 437M + 1)piperazin-1-yl]-5,6,7,8-tetrahydro- 2H-isoquinolin-1-one 724-{5-[(2-hydroxy-2-phenyl- 365(M + 1) 11.75(1H, br s),ethylamino)methyl]furan-2-yl}- 9.14(2H, br s),5,6,7,8-tetrahydro-2H-isoquinolin- 7.46(1H, s), 1-one 7.41-7.31(5H, m),6.67(1H, d, J=3.1 Hz), 6.52(1H, d, J=3.1 Hz), 6.21(1H, d, J=3.4 Hz);4.90(1H, m), 4.30(2H, br s), 3.11(1H, m), 2.99(1H, m), 2.56(2H, m), 2.382H, m), 1.65 4H, m) 73 4-(5-{[(4-methylpiperazin-1- 357(M + 1)ylmethyl)amino]methyl}furan-2-yl)- 5,6,7,8-tetrahydro-2H-isoquinolin-1-one 74 4-(5-{[(morpholin-4-ylmethyl)- 344(M + 1)amino]methyl}furan-2-yl)-5,6,7,8- tetrahydro-2H-isoquinolin-1-one 75N-[4-({[5-(1-oxo-1,2,5,6,7,8- 392(M + 1)hexahydroisoquinolin-4-yl)furan-2- ylmethyl]amino}methyl)phenyl]-acetamide 76 4-(5-thiazolidin-3-ylmethylfuran-2- 317(M + 1)yl)-5,6,7,8-tetrahydro-2H- isoquinolin-1-one 774-(5-{[(1-methyl-1H-pyrazol-4- 339(M + 1) (CDCl3) 7.68(1H,ylmethyl)amino]methyl}furan-2-yl)- s), 7.62(1H, s),5,6,7,8-tetrahydro-2H-isoquinolin- 7.16(1H, s), 1-one 6.42(1H, d, J=3.4Hz), 6.27(1H, d, J=3.4 Hz), 4.18(2H, s), 4.09(2H, s), 3.90(3H, s),2.55(2H, m), 2.39(2H, m), 1.68(4H, m) 784-(5-butylaminomethylfuran-2-yl)- 301(M + 1)5,6,7,8-tetrahydro-2H-isoquinolin- 1-one 794-[5-(benzylaminomethyl)furan-2- 335(M + 1) yl]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one

Synthesis of Examples 80-84 by Acylation of Example 50 with CarboxylicAcids

General Procedure

0.15 mmol of4-(5-aminomethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one aredissolved together with 0.15 mmol of acid chloride or acid anhydride and0.375 mmol of triethylamine in 5 ml of DCM and stirred at 0° C. for 2 h.The reaction mixture is mixed with water and extracted with DCM, and theorganic phase is concentrated and purified by RP-HPLC. Example 84 isisolated as trifluoroacetate.

The following compounds are prepared in accordance with the generalprotocol:

Mass (ES+) NMR(D6-DMSO) Example Name m/z = δ = 802,2,2-trifluoro-N-[5-(1-oxo-1,2,5,6,7,8- 341 11.62(1H, br s),hexahydroisoquinolin-4-yl)furan-2- 9.99(1H, s), ylmethyl]acetamide7.34(1H, s), 6.42(1H, d, J=3.4 Hz), 6.37(1H, d, J=3.4 Hz), 4.42(2H, d,J=5.8 Hz), 2.55(2H, m), 2.37(2H, m), 1.65(4H, m). 813-methyl-N-[5-(1-oxo-1,2,5,6,7,8- 329 hexahydroisoquinolin-4-yl)furan-2-ylmethyl]butyramide 82 N-[5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 3394-yl)furan-2- ylmethyl]furan-2-carboxamide 834-methoxy-N-[5-(1-oxo-1,2,5,6,7,8- 379 11.6(1H, br s);hexahydroisoquinolin-4-yl)furan-2- 8.83(1H, t, J=5.5Hz);ylmethyl]benzamide 7.86(2H, d, J=8.9 Hz); 7.33(1H, s); 7.00(2H, d, J=8.9Hz); 6.39(1H, d, J=3.1 Hz); 6.30(1H, d, J=3.1 Hz); 4.46(2H, d, J=5.5Hz); 3.80(3H, s); 2.55(2H, m); 2.37(2H, m); 1.64(4H, m). 84N-[5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 350 4-yl)furan-2-ylmethyl]nicotinamide

Synthesis of Examples 85-87 by Reacting Example 50 with SulfonylChlorides

General Procedure

0.15 mmol of4-(5-aminomethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one aredissolved together with 0.18 mmol of sulfonyl chloride and 0.375 mmol ofpotassium carbonate in 5 ml of DCM and stirred at RT for 18 h. Thereaction mixture is mixed with water and extracted with DCM, and theorganic phase is concentrated and purified by RP-HPLC. Example 85 isisolated as trifluoroacetate.

Mass (ES+) NMR(D6-DMSO) Example Name m/z = δ = 85N-[5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 5924-yl)furan-2-ylmethyl]- 4-(pyridin-2-yloxy)benzenesulfonamide 863-methoxy-N-[5-(1-oxo-1,2,5,6,7,8- 415hexahydroisoquinolin-4-yl)furan-2- ylmethyl]benzenesulfonamide 87N-(4-{[5-(1-oxo-1,2,5,6,7,8-hexahydroisoquinolin- 442 11.6(1H, br s);4-yl)furan-2- 10.22(1H, s); ylmethyl]sulfamoyl}phenyl)acetamide 8.06(1H,t, J=5.8 Hz); 7.65(4H, m); 7.24(1H, s); 6.26(1H, d, J=3.1 Hz); 6.29(1H,d, J=3.1 Hz); 4.02(2H, d, J=5.8 Hz); 2.45(2H, m); 2.36(2H, m); 2.06(3H,s); 1.63(4H, m).Pharmacological InvestigationsPARP Enzyme Assay

The half-maximum inhibitor concentration is determined by incubating thesubstances to be tested with the DNA-activated, recombinantly expressedand purified PARP-1 enzyme. Specifically, various concentrations of thetest substance are incubated in 50 μl of reaction solution, whichcontains 50 mM Tris, 5 mM MgCl₂, 1 mM DTT, 200 μM NAD, 0.1 mCi/mltritium-labeled NAD, 0.1 mg/ml DNA, 0.1 mg/ml histones, 2 μg/mlrecombinantly expressed human PARP-1 enzyme, pH=8.0, at room temperaturefor 1 hour. The reaction is stopped by adding 150 μl of 20%trichloroacetic acid, and the radiolabeled protein constituents areprecipitated. After incubation on ice for 10 minutes, the labeled,insoluble constituents are separated off through a glass fiber filterand, after washing with 20% trichloroacetic acid three times, theradioactivity incorporated by the PARP-1 enzyme is measured byradioluminescence. Consideration of the incorporation rates determinedin this way as a function of the concentration of the test substanceresults in the half-maximum inhibitor concentration (IC₅₀) as theconcentration of the test substance which reduces the incorporation rateto half the maximum value attainable (incubation without inhibitor).

IC-50 values were determined in this way for the following compounds:

Ex. IC-50 [μM] Ex. IC-50 [μM] Ex. IC-50 [μM] 1 1.31 2 0.27 3 9.83 4 6.355 0.39 6 0.80 7 0.30 8 0.61 9 0.28 10 1.43 11 0.39 12 0.67 13 0.08 141.21 15 0.69 16 0.09 17 0.14 18 0.38 19 0.74 20 1.28 21 10.58 22 0.33 232.01 24 0.22 25 7.70 26 1.47 27 2.54 28 0.40 29 0.56 30 3.35 31 4.80 320.77 33 3.69 34 3.48 35 6.88 36 0.42 37 4.07 38 3.19 39 5.89 40 4.69 413.85 42 1.03 43 0.82 44 8.27 45 1.70 46 3.13 47 3.29 48 3.07 49 5.11 510.59 52 0.33 53 0.24 54 0.30 55 4.54 56 1.45 57 0.42 58 1.27 59 0.99 600.56 61 0.11 62 1.53 63 0.24 64 0.34 65 0.46 66 1.18 67 0.72 68 0.34 692.76 70 0.31 71 1.24 72 0.11 73 0.66 74 0.74 75 0.51 76 0.44 77 0.18 780.25 79 0.15 80 0.54 81 1.07 82 0.46 83 1.25 84 0.79 85 1.63 86 2.48 873.77ATP Consumption Assay in Cardiomyoblasts

The activity of the test substances in cells is ascertained by means ofan ATP consumption assay. For this purpose, rat cardiomyocytes (H9c2cell line) are seeded in a 96-well plate (40 000 cells per well,RPMI1640; 10% FCS) and kept at 37° C. and 5% CO₂ for 16 hours. The cellsare washed with PBS and incubated under identical conditions withvarious concentrations of the test substance in medium for 15 min. Afteraddition of 300 μM H₂O₂, the cells are kept at 37° C., 5% CO₂ for afurther hour and lysed, and the cellular content of ATP is determined bymeans of luciferase reaction. The half-maximum effective concentrationof the substances (EC50) is determined as the concentration at which theATP content of the cells has reached half the value which can bemeasured with a maximally effective concentration of the same substance.

Enzyme Inhibition Assay with Various Substrate Concentrations

Apparent K_(i) values of the test substances are determined in anenzymatic assay using the purified human PARP-1 enzyme. Specifically,various concentrations of the tritium-labeled substrate NAD areincubated with an identical concentration of the test substance in 50 μlof reaction solution, which contains 50 mM tris, 5 mM MgCl2, 1 mM DTT,0.1 mg/ml DNA, 0.1 mg/ml histones, 2 μg/ml recombinantly expressed humanPARP-1 enzyme, pH=8.0, at room temperature for 10 min. The reaction isstopped by adding 150 μl of 20% trichloroacetic acid, and theradiolabeled protein constituents are precipitated. After incubation onice for 10 minutes, the labeled, insoluble constituents are separatedoff through a glass fiber filter and, after washing with 20%trichloroacetic acid three times, the radioactivity incorporated by thePARP-1 enzyme is measured by radioluminescence. Evaluation of theincorporation rates determined in this way as a function of theconcentration of the substrate NAD affords the apparent K_(i) valuesaccording to Michaelis-Menten kinetics, assuming that the mechanism ofinhibition is purely competitive.

EC-50 values and apparent K_(i) values are determined in this way forall the following selected compounds:

Ex. EC-50 [μM] app. K_(i) [nM] Ex. EC-50 [μM] app. K_(i) [nM] 9 1.57 1654 0.33 15 16 0.2 54 72 0.38 24 24 — 31 78 0.52 40

1. A compound of the formula (I)

in which the meanings are: X is a single bond, O, S, NH orN(C₁-C₃-alkyl); R1 is hydrogen, fluorine, chlorine, —CN, methoxy, —OCF₃or C₁-C₃-alkyl which is optionally substituted by hydroxy, chlorine,methoxy or one, two or three fluorine atoms; R2 is hydrogen, fluorine,—CN, hydroxy, methoxy, —OCF₃, —NH₂, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂or C₁-C₃-alkyl which is optionally substituted by hydroxy, chlorine,methoxy or one, two or three fluorine atoms; R3 is —(C₁-C₃-alkyl)—NR4R5,—SO₂NR4R5, —C(O)NR4R5, —C(H)═N—OR9, —C(O)R6, —NHC(O)R6,—(C₁-C₃-alkyl)—NHC(O)R6, —NHSO₂R6, —(C₁-C₃-alkyl)—NHSO₂R6 or —CH(OH)R7;R4 and R5 are independently of one another selected from the groupconsisting of: hydrogen; unsubstituted or at least monosubstitutedC₁-C₁₀-alkyl, C₂-C₆-alkenyl, C₂-C₆-alkynyl, aryl, heteroaryl andheterocyclyl, where the substituents are selected from the groupconsisting of: aryl, heteroaryl, heterocyclyl, —O-aryl, fluorine,chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8,—NHC(O)(C₁-C₃-alkyl), —NH₂, hydroxy, C₁-C₆-alkyl, C₁-C₃-alkoxy,—NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —NH-aryl, —NH-heteroaryl,—NH—C(O)-heteroaryl, —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and—NH—SO₂(C₁-C₃-alkyl), and the aryl, heteroaryl and heterocyclylfragments of these substituents may in turn be at least monosubstitutedby fluorine, chlorine, bromine, oxo, —CF₃, —OCF₃, —NO₂, —CN, aryl,heteroaryl, —NHC(O)(C₁-C₃-alkyl), —COOH, hydroxy, C₁-C₃-alkyl,C₁-C₃-alkoxy, —SO₂NH₂, —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂,—C(O)NH₂, —C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl),—NH₂, —NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂; or R4 and R5 form togetherwith the nitrogen atom to which they are bonded unsubstituted or atleast monosubstituted heterocyclyl, where the substituents are selectedfrom the group consisting of: aryl, heteroaryl, heterocyclyl, oxo,fluorine, chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8,—NHC(O)(C₁-C₃-alkyl), —NH₂, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,—NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and—NH—SO₂(C₁-C₃-alkyl), and, of these substituents, aryl, heterocyclyl andheteroaryl in turn may be at least monosubstituted by fluorine,chlorine, bromine, hydroxy, C₁-C₃-alkyl or C₁-C₃-alkoxy; R6 isunsubstituted or at least monosubstituted C₁-C₆-alkyl, phenyl,heteroaryl or heterocyclyl, where the substituents are selected from thegroup consisting of: fluorine, chlorine bromine, aryl, heterocyclyl,heteroaryl, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8, —NHC(O)(C₁-C₃-alkyl), —NH₂,hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —O-heteroaryl, —O-aryl,—NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and—NH—SO₂(C₁-C₃-alkyl), and the aryl, heterocyclyl and heteroarylfragments of these substituents may in turn be at least monosubstitutedby fluorine, chlorine, bromine, hydroxy, C₁-C₃-alkyl or C₁-C₃-alkoxy; R7is selected from the group consisting of: hydrogen; unsubstituted or atleast monosubstituted C₁-C₆-alkyl, phenyl and heteroaryl, where thesubstituents are selected from the group consisting of: fluorine,chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8,—NHC(O)(C₁-C₃-alkyl), —NH₂, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,—NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂NH₂, —SO₂(C₁-C₃-alkyl) and—NH—SO₂(C₁-C₃-alkyl); R8 is C₁-C₃-alkoxy, —O-phenyl, C₁-C₃-alkyl, —NH₂,—NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂ or phenyl, and the above phenylfragments may in turn be at least monosubstituted by fluorine, chlorine,bromine, oxo, —CF₃, —OCF₃, —NO₂, —CN, aryl, heteroaryl,—NHC(O)(C₁-C₃-alkyl), —COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,—SO₂NH₂, —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂,—C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), —NH₂,—NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂ R9 is selected from the groupconsisting of: hydrogen; unsubstituted or at least monosubstitutedC₁-C₆-alkyl and phenyl, where the substituents are selected from thegroup consisting of: fluorine, chlorine, bromine, aryl, heterocyclyl,heteroaryl, —CF₃, —OCF₃, —NO₂, —CN, —C(O)R8, —NHC(O)(C₁-C₃-alkyl),C₁-C₃-alkyl, C₁-C₃-alkoxy, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SO₂NH₂,—SO₂(C₁-C₃-alkyl) and —NH—SO₂(C₁-C₃-alkyl), and, of these substituents,aryl, heterocyclyl and heteroaryl may in turn be at leastmonosubstituted by fluorine, chlorine, bromine, C₁-C₃-alkyl orC₁-C₃-alkoxy; Ar is unsubstituted or at least monosubstituted aryl orheteroaryl, where the substituents are selected from the groupconsisting of: fluorine, chlorine, bromine, —CF₃, —OCF₃, —NO₂, —CN,—C(O)R8, —NH₂, —NHC(O)(C₁-C₆-alkyl), hydroxy, C₁-C₆-alkyl, C₁-C₆-alkoxy,—CH₂—CH₂—CH₂—, —CH₂—O—C(O)—, —CH₂—C(O)—O—, —CH₂—NH—C(O)—,—CH₂—N(CH₃)—C(O)—, —CH₂—C(O)—NH—, —NH(C₁-C₆-alkyl), —N(C₁-C₆-alkyl)₂,—SO₂(C₁-C₆-alkyl), heterocyclyl, heteroaryl, aryl and R3, and, of thesesubstituents, heterocyclyl, aryl and heteroaryl may in turn be at leastmonosubstituted by C₁-C₆-alkyl, C₁-C₆-alkoxy, fluorine, chlorine,bromine, trifluoromethyl, trifluoromethoxy or OH; heteroaryl is a 5 to10-membered, aromatic, mono- or bicyclic heterocycle which comprises oneor more heteroatoms selected from N, O and S; aryl is a 5 to10-membered, aromatic, mono- or bicycle; and heterocyclyl is a 5 to10-membered, non-aromatic, mono- or bicyclic heterocycle which comprisesone or more heteroatoms selected from N, O and S; or a physiologicallytolerated salt thereof. provided that Ar is not unsubstituted phenylwhen X is a single bond.
 2. A compound as claimed in claim 1, in whichthe meanings in the formula (I) are: X is a single bond, NH orN(C₁-C₃-alkyl); R1 is hydrogen or C₁-C₃-alkyl which is optionallysubstituted by hydroxy, chlorine, methoxy or one, two or three fluorineatoms; R2 is hydrogen, fluorine, —OCF₃, hydroxy, methoxy, —NH₂ orC₁-C₃-alkyl; R3 is —CH₂—NR4R5, —SO₂NR4R5, —C(O)NR4R5, —CH₂—NHC(O)R6,—CH₂—NHSO₂R6 or —CH(OH)R7; R4 and R5 are independently of one anotherselected from the group consisting of: hydrogen; unsubstituted or atleast monosubstituted C₁-C₁₀-alkyl, C₂-C₆-alkenyl, phenyl, indanyl,heterocyclyl and heteroaryl, where the substituents are selected fromthe group consisting of: phenyl, heteroaryl, heterocyclyl, —O-phenyl,fluorine, —CN, —C(O)NH₂, —C(O)(C₁-C₃-alkyl), —C(O)-phenyl,—N(C₁-C₃-alkyl)₂, —NH(C₁-C₃-alkyl), —NH₂, —NH-heteroaryl,—NH—C(O)-heteroaryl, C₁-C₆-alkyl, C₁-C₃-alkoxy and hydroxy, and thephenyl, heterocyclyl and heteroaryl fragments of these substituents mayin turn be at least monosubstituted by fluorine, chlorine, bromine, oxo,—CF₃, —OCF₃, —NO₂, —CN, phenyl, pyrimidinyl, —NHC(O)(C₁-C₃-alkyl),—COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂, —SO₂NH(C₁-C₃-alkyl),—SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂, —C(O)NH(C₁-C₃-alkyl),—C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), —NH₂, —NH(C₁-C₃-alkyl) or—N(C₁-C₃-alkyl)₂; or R4 and R5 form together with the nitrogen atom towhich they are bonded unsubstituted or at least monosubstitutedheterocyclyl, where the substituents are selected from the groupconsisting of: phenyl, heteroaryl, heterocyclyl, oxo, fluorine,chlorine, —C(O)(C₁-C₃-alkyl), —C(O)-phenyl and hydroxy, and the phenyl,heterocyclyl and heteroaryl fragments of these substituents may in turnbe at least monosubstituted by fluorine or C₁-C₃-alkyl; R6 isunsubstituted or at least monosubstituted C₁-C₆-alkyl, phenyl orheteroaryl, where the substituents are selected from the groupconsisting of: fluorine, chlorine, bromine, —CF₃, —OCF₃,—NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —O-heteroaryl,phenyl, —NH₂, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂ and heterocyclyl, andthe phenyl, heteroaryl and heterocyclyl fragments of these substituentsmay in turn be at least monosubstituted by fluorine, chlorine, bromine,hydroxy, C₁-C₃-alkyl or C₁-C₃-alkoxy; R7 is selected from the groupconsisting of: hydrogen; unsubstituted or at least monosubstitutedC₁-C₆-alkyl, phenyl and pyridinyl, where the substituents are selectedfrom the group consisting of: fluorine, chlorine, bromine, hydroxy,C₁-C₃-alkyl and C₁-C₃-alkoxy; Ar is unsubstituted or at leastmonosubstituted phenyl or heteroaryl, where the substituents areselected from the group consisting of: fluorine, chlorine, —CF₃, —OCF₃,C(O)(C₁-C₃-alkyl), —NH₂, —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl,C₁-C₃-alkoxy, —CH₂-CH₂-CH₂—, —CH₂—O—C(O)—, —CH₂-C(O)—O—, —CH₂—NH—C(O)—,—CH₂—N(CH₃)—C(O)—, —CH₂-C(O)—NH—, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂,—SO₂(C₁-C₃-alkyl), heterocyclyl, heteroaryl and R3; and, of thesesubstituents, heterocyclyl and heteroaryl may in turn be at leastmonosubstituted by C₁-C₃-alkyl, C₁-C₃-alkoxy, fluorine, chlorine,bromine, trifluoromethyl, trifluoromethoxy or OH; heteroaryl ispyridinyl, thienyl, pyrimidinyl, imidazolyl, furanyl, indolyl,benzimidazolyl, pyrazolyl, 1,3-benzodioxolyl, triazolyl, thiazolyl,isoxazolyl, pyrrolyl, pyrazinyl, oxazolyl, pyridazinyl, quinolinyl,isoquinolyl, benzofuranyl, 3-oxo-1,3-dihydroisobenzofuranyl or4,5,6,7-tetrahydrobenzothiazolyl; and heterocyclyl is morpholinyl,pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiazolidinyl,dihydroisoxazolyl, piperazinyl or tetrahydrofuranyl; or aphysiologically tolerated salt thereof.
 3. A compound as claimed inclaim 2, in which the meanings in the formula (I) are: X is a singlebond, NH or N(C₁-C₃-alkyl); R1 is hydrogen or C₁-C₃-alkyl which isoptionally substituted by hydroxy, chlorine, methoxy or one, two orthree fluorine atoms; R2 is hydrogen, fluorine, —OCF₃, hydroxy, methoxy,—NH₂ or C₁-C₃-alkyl; R3 is —CH₂—NR4R5, —SO₂NR4R5, —C(O)NR4R5,—CH₂—NHC(O)R6, —CH₂—NHSO₂R6 or —CH(OH)R7; R4 and R5 are independently ofone another selected from the group consisting of: hydrogen;unsubstituted or at least monosubstituted C₁-C₁₀-alkyl, C₂-C₆-alkenyl,phenyl, indanyl, heterocyclyl and heteroaryl, where the substituents areselected from the group consisting of: phenyl, heteroaryl, heterocyclyl,—O-phenyl, fluorine, —CN, —C(O)NH₂, —C(O)(C₁-C₃-alkyl), —C(O)-phenyl,—N(C₁-C₃-alkyl)₂, —NH(C₁-C₃-alkyl), —NH₂, —NH-heteroaryl,—NH—C(O)-heteroaryl, C₁-C₆-alkyl, C₁-C₃-alkoxy and hydroxy, and thephenyl, heterocyclyl and heteroaryl fragments of these substituents mayin turn be at least monosubstituted by fluorine, chlorine, bromine, oxo,—CF₃, —OCF₃, —NO₂, —CN, phenyl, pyrimidinyl, —NHC(O)(C₁-C₃-alkyl),—COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂, —SO₂NH(C₁-C₃-alkyl),—SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂, —C(O)NH(C₁-C₃-alkyl),—C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), —NH₂, —NH(C₁-C₃-alkyl) or—N(C₁-C₃-alkyl)₂; or R4 and R5 form together with the nitrogen atom towhich they are bonded unsubstituted or at least monosubstitutedheterocyclyl, where the substituents are selected from the groupconsisting of: phenyl, heteroaryl, heterocyclyl, oxo, fluorine,chlorine, —C(O)(C₁-C₃-alkyl), —C(O)-phenyl and hydroxy, and the phenyl,heterocyclyl and heteroaryl fragments of the substituents may in turn beat least monosubstituted by fluorine or C₁-C₃-alkyl; R6 is CF₃ orunsubstituted or at least monosubstituted C₁-C₆-alkyl, pyridinyl,furanyl or phenyl, where the substituents are selected from the groupconsisting of: fluorine, —NHC(O)(C₁-C₃-alkyl), hydroxy C₁-C₃-alkyl,C₁-C₃-alkoxy and —O-pyridinyl; R7 is selected from the group consistingof: hydrogen; unsubstituted or at least monosubstituted C₁-C₆-alkyl,phenyl and pyridinyl, where the substituents are selected from the groupconsisting of: fluorine, chlorine, bromine, hydroxy, C₁-C₃-alkyl andC₁-C₃-alkoxy; Ar is unsubstituted or at least monosubstituted phenyl,thienyl, furanyl or pyridinyl, where the substituents are selected fromthe group consisting of: fluorine, chlorine, —CF₃, —OCF₃,C(O)(C₁-C₃-alkyl), —NH₂, —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl,C₁-C₃-alkoxy, —CH₂—CH₂—CH₂—, —CH₂—O—C(O)—, —CH₂-C(O)—O—, —CH₂—NH—C(O)—,—CH₂—N(CH₃)—C(O)—, —CH₂—C(O)—NH—, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂,—SO₂(C₁-C₃-alkyl) and R3; heteroaryl is pyridinyl, thienyl, pyrimidinyl,imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl,1,3-benzodioxolyl, triazolyl, thiazolyl, isoxazolyl, pyrrolyl,pyrazinyl, oxazolyl, pyridazinyl, quinolinyl, isoquinolyl, benzofuranyl,3-oxo-1,3-dihydroisobenzofuranyl or 4,5,6,7-tetrahydrobenzothiazolyl;and heterocyclyl is morpholinyl, pyrrolidinyl, piperidinyl,tetrahydropyranyl, thiazolidinyl, dihydroxyisoxazolyl, piperazinyl ortetrahydrofuranyl; or a physiologically tolerated salt thereof.
 4. Acompound as claimed in claim 3, in which the meanings in the formula (I)are: X is a single bond, NH or N(C₁-C₃-alkyl); R1 is hydrogen orC₁-C₃-alkyl; R2 is hydrogen; R3 is —CH₂—NR4R5, —CH₂—NHC(O)R6,—CH₂—NHSO₂R6, —C(O)NR4R5 or —CH(OH)R7; R4 is selected from the groupconsisting of: hydrogen, unsubstituted or at least monosubstitutedC₁-C₁₀-alkyl, C₁-C₆-alkenyl, phenyl, indanyl, heterocyclyl andheteroaryl, where the substituents are selected from the groupconsisting of: phenyl, heteroaryl, heterocyclyl, —O-phenyl, fluorine,—CN, —C(O)NH₂, —C(O)(C₁-C₃-alkyl), —C(O)-phenyl, —N(C₁-C₃-alkyl)₂,—NH(C₁-C₃-alkyl), —NH₂, —NH-heteroaryl, —NH—C(O)-heteroaryl,C₁-C₆-alkyl, C₁-C₃-alkoxy and hydroxy, and the phenyl, heterocyclyl andheteroaryl fragments of these substituents may in turn by fluorine,chlorine, bromine, oxo, —CF₃, —OCF₃, —NO₂, —CN, phenyl, pyridinyl,—NHC(O)(C₁-C₃-alkyl), —COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,—SO₂NH₂, —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂,—C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), —NH₂,—NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)₂; and R5 is hydrogen; or R4 and R5form together with the nitrogen atom to which they are bondedunsubstituted or at least monosubstituted heterocyclyl, where thesubstituents are selected from the group consisting of: phenyl,heteroaryl, heterocyclyl, oxo, fluorine, chlorine, —C(O)(C₁-C₃-alkyl),—C(O)-phenyl and hydroxy, and the phenyl, heterocyclyl and heteroarylfragments of these substituents may in turn be at least monosubstitutedby fluorine or C₁-C₃-alkyl; R6 is CF₃ or unsubstituted or at leastmonosubstituted C₁-C₆-alkyl, pyridinyl, furanyl or phenyl, where thesubstituents are selected from the group consisting of: fluorine,—NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy and—O-pyridinyl; R7 is selected from the group consisting of: hydrogen;unsubstituted or at least monosubstituted C₁-C₆-alkyl, phenyl andpyridinyl, where the substituents are selected from the group consistingof: fluorine, chlorine, bromine, hydroxy, C₁-C₃-alkyl and C₁-C₃-alkoxy;Ar is monosubstituted phenyl, thienyl, furanyl or pyridinyl, where thesubstituent is selected from the group consisting of: fluorine,chlorine, —CF₃, —OCF₃, —C(O)(C₁-C₃-alkyl), —NH₂, —NHC(O)(C₁-C₃-alkyl),hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂,—SO₂(C₁-C₃-alkyl) and R3; and the substituent and X are in the metaposition relative to one another; heteroaryl is pyridinyl, thienyl,pyrimidinyl, imidazolyl, furanyl, benzimidazolyl, pyrazolyl, thiazolyl,isoxazolyl, pyrrolyl, pyrazinyl, 3-oxo-1,3-dihydroisobenzofuranyl or4,5,6,7-tetrahydrobenzothiazolyl; and heterocyclyl is morpholinyl,pyrrolidinyl, piperidinyl, tetrahydropyranyl, thiazolidinyl,dihydroisoxazolyl, piperazinyl or tetrahydrofuranyl; or aphysiologically tolerated salt thereof.
 5. A compound as claimed inclaim 4, in which the meanings in the formula (I) are: X is a singlebond or NH; R1 is hydrogen or C₁-C₃-alkyl; R2 is hydrogen; R3 is—CH₂—NR4R5, —C(O)NR4R5 or —CH(OH)R7; R4 is selected from the groupconsisting of; hydrogen; unsubstituted or at least monosubstitutedC₁-C₁₀-alkyl, cyclohexenyl, indanyl, phenyl, pyrrolidinyl, pyrrolyl,pyrazolyl, furanyl and piperidinyl, where the substituents are selectedfrom the group consisting of: fluorine, —CN, —C(O)NH₂, —O-phenyl,—C(O)-phenyl, —N(CH₃)₂, C₁-C₃-alkyl, C₁-C₃-alkoxy, hydroxy,unsubstituted or at least monosubstituted phenyl, pyridinyl, thienyl,pyrimidinyl, imidazolyl, furanyl, indolyl, benzimidazolyl, pyrazolyl,morpholinyl, pyrrolidinyl, 1,3-benzodioxolyl, piperidinyl,tetrahydropyranyl, triazolyl, thiazolyl, thiazolidinyl, isoxazolyl anddihydroisoxazolyl, the substituents of which are in turn selected fromthe group consisting of: fluorine, chlorine, oxo, CF₃, —OCF₃, —NO₂,phenyl, pyridinyl, —NHC(O)CH₃, —COOH, hydroxy, C₁-C₃-alkyl,C₁-C₃-alkoxy, —SO₂NH₂, —C(O)NH₂ and —N(CH₃)₂; and R5 is hydrogen; or R4and R5 form together with the nitrogen atom to which they are bonded aradical selected from the group consisting of: unsubstituted or at leastmonosubstituted piperidinyl, pyrrolidinyl, morpholinyl and piperazinyl,where the substituents are selected from the group consisting of:fluorine, —C(O)(C₁-C₃-alkyl), oxo, C₁-C₃-alkyl, hydroxy, unsubstitutedor at least monosubstituted phenyl, imidazolyl, pyridinyl, pyrimidinyl,piperidinyl and pyrrolidinyl, the substituents of which are in turnfluorine or C₁-C₃-alkyl; R7 is hydrogen; and Ar is monosubstitutedphenyl, thienyl, furanyl or pyridinyl, where the substituent is selectedfrom the group consisting of: fluorine, chlorine, —CF₃, —OCF₃,—C(O)(C₁-C₃-alkyl), —NH₂, —NHC(O)(C₁-C₃-alkyl), hydroxy, C₁-C₃-alkyl,C₁-C₃-alkoxy, —NH(C₁-C₃-alkyl), —N(C₁-C₃-alkyl)₂, —SC₂(C₁-C₃-alkyl) andR3; and the substituent and X are in the meta position relative to oneanother; or a physiologically tolerated salt thereof.
 6. A compound asclaimed in claim 5, in which the meanings in the formula (I) are: X is asingle bond or NH; R1 is hydrogen or C₁-C₃-alkyl; R2 is hydrogen; R3 is—CH₂—NR4R5; R4 is unsubstituted or at least monosubstituted C₁-C₆-alkyl,where the substituents are selected from the group consisting of:—N(CH₃)₂, hydroxy, unsubstituted or at least monosubstituted phenyl,pyridinyl, imidazolyl, indolyl, benzimidazolyl, pyrazolyl andpyrrolidinyl, the substituents of which are in turn selected from thegroup consisting of: —NHC(O)CH₃, C₁-C₃-alkyl, C₁-C₃-alkoxy, —SO₂NH₂ and—C(O)NH₂; and R5 is hydrogen; or R4 and R5 form together with thenitrogen atom to which they are bonded a radical selected from the groupconsisting of: unsubstituted or at least monosubstituted pyrrolidinyl,piperidinyl and piperazinyl, where the substituents are selected fromthe group consisting of: C₁-C₃-alkyl, hydroxy and pyrrolidinyl; and Aris monosubstituted phenyl, thienyl, furanyl or pyridinyl, where thesubstituent is selected from the group consisting of: fluorine,chlorine, —OCF₃, —C(O)CH₃, —NHC(O)CH₃, hydroxy, —N(CH₃)₂, ethoxy,—SO₂CH₃ and R3; and the substituent and X are in the meta positionrelative to one another; or a physiologically tolerated salt thereof. 7.A compound as claimed in claim 5, selected from the group consisting of:4-(3-methanesulfonylphenylamino)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-(3-acetylphenylamino)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-(5-butylaminomethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,3-methyl-4-(5-pyrrolidin-1-ylmethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-[5-(3-hydroxypyrrolidin-1-ylmethyl)furan-2-yl]-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-(5-{[(4-pyrrolidin-1-ylpiperidin-1-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-{5-[(2-dimethylaminoethylamino)methyl]furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-{5-[(2-hydroxy-2-phenylethylamino)methyl]furan-2-yl}-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-(5-{[(4-methylpiperazin-1-ylmethyl)amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-(5-{[(1-methyl-1H-pyrazol-4-ylmethyl)-amino]methyl}furan-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-one,4-(5-butylaminomethylfuran-2-yl)-5,6,7,8-tetrahydro-2H-isoquinolin-1-oneand4-(5-hydroxymethylfuran-2-yl)-3-methyl-5,6,7,8-tetrahydro-2H-isoquinolin-1-one;or a physiologically tolerated salt thereof.
 8. A pharmaceuticalcomposition comprising an effective amount of at least one compound asclaimed in claim 1 and a physiologically acceptable carrier.
 9. Apharmaceutical composition as claimed in claim 8, wherein thepharmaceutical composition is in the form of a pill, tablet, coatedtablet, suckable tablet, granules, capsule, hard or soft gelatincapsule, aqueous solution, alcoholic solution, oily solution, syrup,emulsion, suspension, suppository, pastille, solution for injection orinfusion, ointment, tincture, cream, lotion, dusting powder, spray,transdermal therapeutic system, nasal spray, aerosol, aerosol mixture,microcapsule, implant, rod or patch.
 10. A method for preparing acompound of the formula (Ib),

(1) is reacted with a suitable amine in the presence of a reducing agentwhen R″ is —CHO and R3 is —CH₂—NR4R5, or (2) is reduced with a suitablereducing agent when R″ is —CHO and R3 is —CH₂OH, or (3) is reacted byreductive amination with ammonium acetate, with subsequent couplingreaction with a suitable acid chloride, a suitable acid or a suitablesulfonyl chloride when R″ is —CHO and R3 is —CH₂NHC(O)R6 or —CH₂NHSO₂R6,or (4) is reacted with a suitable amine in the presence of a condensingagent when R″ is —COOH and R3 is —C(O)NR4R5, wherein R1 is hydrogen,fluorine, chlorine, —CN, methoxy, —OCF3 or C1-C3-alkyl which isoptionally substituted by hydroxy, chlorine, methoxy or one, two orthree fluorine atoms; R2 is hydrogen, fluorine, —CN, hydroxy, methoxy,—OCF3, —NH2, —NH(C1—C3-alkyl), —N(C1-C3-alkyl)2 or C1-C3-alkyl which isoptionally substituted by hydroxy, chlorine, methoxy or one, two orthree fluorine atoms; R3 is —(C1-C3-alkyl)—NR4R5, —SO2NR4R5, —C(O)NR4R5,—C(H)═N—OR9, —C(O)R6, —NHC(O)R6, —(C1-C3-alkyl)—NHC(O)R6, —NHSO2R6,—(C1-C3-alkyl)—NHSO2R6 or —CH(OH)R7; R4 and R5 are independently of oneanother selected from the group consisting of: hydrogen; unsubstitutedor at least monosubstituted C1-C10-alkyl, C2-C6-alkenyl, C2-C6-alkynyl,aryl, heteroaryl and heterocyclyl, where the substituents are selectedfrom the group consisting of: aryl, heteroaryl, heterocyclyl, —O-aryl,fluorine, chlorine, bromine, —CF3, —OCF3, —NO2, —CN, —C(O)R8,—NHC(O)(C1-C3-alkyl), —NH2, hydroxy, C1-C6-alkyl, C1-C3-alkoxy,—NH(C1-C3-alkyl), —N(C1-C3-alkyl)2, —NH-aryl, —NH-heteroaryl,—NH—C(O)-heteroaryl, —SO2NH2, —SO2(C1-C3-alkyl) and—NH—SO2(C1-C3-alkyl), and the aryl, heteroaryl and heterocyclylfragments of these substituents may in turn be at least monosubstitutedby fluorine, chlorine, bromine, oxo, —CF3, —OCF3, —NO2, —CN, aryl,heteroaryl, —NHC(O)(C1-C3-alkyl), —COOH, hydroxy, C1-C3-alkyl,C1-C3-alkoxy, —SO2NH2, —SO2NH(C1-C3-alkyl), —SO2N(C1-C3-alkyl)2,—C(O)NH2, —C(O)NH(C1-C3-alkyl), —C(O)N(C1-C3-alkyl)2, —SO2(C1-C3-alkyl),—NH2, —NH(C1-C3-alkyl) or —N(C1-C3-alkyl)2; or R4 and R5 form togetherwith the nitrogen atom to which they are bonded unsubstituted or atleast monosubstituted heterocyclyl, where the substituents are selectedfrom the group consisting of: aryl, heteroaryl, heterocyclyl, oxo,fluorine, chlorine, bromine, —CF3, —OCF3, —NO2, —CN, —C(O)R8,—NHC(O)(C1-C3-alkyl), —NH2, hydroxy, C1-C3-alkyl, C1-C3-alkoxy,—NH(C1-C3-alkyl), —N(C1-C3-alkyl)2, —SO2NH2, —SO2(C1-C3-alkyl) and—NH—SO2(C1-C3-alkyl), and, of these substituents, aryl, heterocyclyl andheteroaryl in turn may be at least monosubstituted by fluorine,chlorine, bromine, hydroxy, C1-C3-alkyl or C1-C3-alkoxy; R6 isunsubstituted or at least monosubstituted C1-C6-alkyl, phenyl,heteroaryl or heterocyclyl, where the substituents are selected from thegroup consisting of: fluorine, chlorine, bromine, aryl, heterocyclyl,heteroaryl, —CF3, —OCF3, —NO2, —CN, —C(O)R8, —NHC(O)(C1-C3-alkyl), —NH2,hydroxy, C1-C3-alkyl, C1-C3-alkoxy, —O-heteroaryl, —O-aryl,—NH(C1-C3-alkyl), —N(C1-C3-alkyl)2, —SO2NH2, —SO2(C1-C3-alkyl) and—NH—SO2(C1—3-alkyl), and the aryl, heterocyclyl and heteroaryl fragmentsof these substituents may in turn be at least monosubstituted byfluorine, chlorine, bromine, hydroxy, C1-C3-alkyl or C1-C3-alkoxy; R7 isselected from the group consisting of: hydrogen; unsubstituted or atleast monosubstituted C1-C6-alkyl, phenyl and heteroaryl, where thesubstituents are selected from the group consisting of: fluorine,chlorine, bromine, —CF3, —OCF3, —NO2, —CN, —C(O)R8,—NHC(O)(C1-C3-alkyl), —NH2, hydroxy, C1-C3-alkyl, C1-C3-alkoxy,—NH(C1-C3-alkyl), —N(C1-C3-alkyl)2, —SO2NH2, —SO2(C1-C3-alkyl) and—NH—SO2(C1-C3-alkyl); R8 is C1-C3-alkoxy, —O-phenyl, C1-C3-alkyl, —NH2,—NH(C1-C3-alkyl), —N(C1-C3-alkyl)2 or phenyl, and the above phenylfragments may in turn be at least monosubstituted by fluorine, chlorine,bromine, oxo, —CF₃, —OCF₃, —NO₂, —CN, aryl, heteroaryl,—NHC(O)(C₁-C₃-alkyl), —COOH, hydroxy, C₁-C₃-alkyl, C₁-C₃-alkoxy,—SO₂NH₂, —SO₂NH(C₁-C₃-alkyl), —SO₂N(C₁-C₃-alkyl)₂, —C(O)NH₂,—C(O)NH(C₁-C₃-alkyl), —C(O)N(C₁-C₃-alkyl)₂, —SO₂(C₁-C₃-alkyl), —NH₂,—NH(C₁-C₃-alkyl) or —N(C₁-C₃-alkyl)2; R9 is selected from the groupconsisting of: hydrogen; unsubstituted or at least monosubstitutedC₁-C₆-alkyl and phenyl, where the substituents are selected from thegroup consisting of: fluorine, chlorine, bromine, aryl, heterocyclyl,heteroaryl, —CF3, —OCF3, —NO2, —CN, —C(O)R8, —NHC(O)(C1-C3-alkyl),C1-C3-alkyl, C1-C3-alkoxy, —NH(C1-C3-alkyl), —N(C1-C3-alkyl)2, —SO2NH2,—SO2(C1-C3-alkyl) and —NH—SO2(C1-C3-alkyl), and, of these substituents,aryl, heterocyclyl and heteroaryl may in turn be at leastmonosubstituted by fluorine, chlorine, bromine, C1-C3-alkyl orC1-C3-alkoxy; Ar is unsubstituted or at least monosubstituted aryl orheteroaryl, where the substituents are selected from the groupconsisting of: fluorine, chlorine, bromine, —CF3, —OCF3, —NO2, —CN,—C(O)R8, —NH2, —NHC(O)(C1—C6-alkyl), hydroxy, C1-C6-alkyl, C1-C6-alkoxy,—CH2—CH2—CH2—, —CH2—O—C(O)—, —CH2-C(O)—O—, —CH2—NH—C(O)—,—CH2—N(CH3)—C(O)—, —CH2-C(O)—NH—, —NH(C1-C6-alkyl), —N(C1-C6-alkyl)2,—SO2(C1-C6-alkyl), heterocyclyl, heteroaryl, aryl and R3, and, of thesesubstituents, heterocyclyl, aryl and heteroaryl may in turn be at leastmonosubstituted by C1-C6-alkyl, C1-C6-alkoxy, fluorine, chlorine,bromine, trifluoromethyl, trifluoromethoxy or OH; heteroaryl is a 5 to10-membered, aromatic, mono- or bicyclic heterocycle which comprises oneor more heteroatoms selected from N, O and S; aryl is a 5 to10-membered, aromatic, mono- or bicycle; and heterocyclyl is a 5 to10-membered, non-aromatic, mono- or bicyclic heterocycle which comprisesone or more heteroatoms selected from N, O and S.